Modern Drug Synthesis E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Wiley Series on Drug Synthesis
- Sprache: Englisch
Following Contemporary Drug Synthesis and The Art of Drug Synthesis (Wiley, 2004 and 2007), two well-received works, is this new book that demystifies the process of modern drug discovery for practitioners and students. An enhanced introduction covers areas such as background, pharmacology, SAR, PK/PD, efficacy, and safety. Focusing on the advantages of process synthesis versus the discovery synthetic route, Modern Drug Synthesis features authoritative coverage by distinguished editors and authors (some chapter authors are the actual inventor of the drug) of twenty different drug molecules.
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Seitenzahl: 475
Veröffentlichungsjahr: 2013
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Contents
Cover
Half Title page
Title page
Copyright page
Preface
Contributors
Part I: Infectious Diseases
Chapter 1: Raltegravir (Isentress): The First-in-Class HIV-1 Integrase Inhibitor
1.1 Background
1.2 Pharmacology
1.3 Structure–Activity Relationship (SAR)
1.4 Pharmacokinetics and Drug Metabolism
1.5 Efficacy and Safety
1.6 Syntheses
1.7 References
Chapter 2: Maraviroc (Selzentry): The First-in-Class CCR5 Antagonist for the Treatment of HIV
2.1 Background
2.2 Structure–Activity Relationship (SAR)
2.3 Pharmacokinetics and Safety
2.4 Syntheses
2.5 References
Chapter 3: Darunavir (Prezista): A HIV-1 Protease Inhibitor for Treatment of Multidrug-Resistant HIV
3.1 Background
3.2 Structure–Activity Relationship and Darunavir Derivatives
3.3 Pharmacology
3.4 Pharmacokinetics and Drug Metabolism
3.5 Efficacy and Safety
3.6 Syntheses
3.7 Conclusion
3.8 References
Part II: Cancer
Chapter 4: Decitabine (Dacogen): A DNA Methyltransferase Inhibitor for Cancer
4.1 Background
4.2 Pharmacology
4.3 Structure–Activity Relationship (SAR)
4.4 Pharmacokinetics and Drug Metabolism
4.5 Efficacy and Safety
4.6 Syntheses
4.7 References
Chapter 5: Capecitabine (Xeloda): An Oral Chemotherapy Agent
5.1 Background
5.2 Pharmacology
5.3 Structure–Activity Relationship (SAR)
5.4 Pharmacokinetics and Efficacy
5.5 Syntheses
5.6 References
Chapter 6: Sorafenib (Nexavar): A Multikinase Inhibitor for Advanced Renal Cell Carcinoma and Unresectable Hepatocellular Carcinoma
6.1 Background
6.2 Pharmacology
6.3 Structure–Activity Relationship (SAR)
6.4 Pharmacokinetics and Drug Metabolism
6.5 Efficacy and Safety
6.6 Syntheses
6.7 References
Chapter 7: Sunitinib (Sutent): An Angiogenesis Inhibitor
7.1 Background
7.2 Discovery and Development of Sunitinib
7.3 Syntheses
7.4 References
Chapter 8: Bortezomib (Velcade): A First-in-Class Proteasome Inhibitor
8.1 Background
8.2 Pharmacology
8.3 Structure–Activity Relationship (SAR)
8.4 Pharmacokinetics and Drug Metabolism
8.5 Efficacy and Safety
8.6 Syntheses
8.7 References
Chapter 9: Pazopanib (Votrient): A VEGFR Tyrosine Kinase Inhibitor for Cancer
9.1 Background
9.2 Pharmacology
9.3 Structure–Activity Relationship (SAR)
9.4 Pharmacokinetics and Drug Metabolism
9.5 Efficacy and Safety
9.6 Synthesis
9.7 Other VEGFR Inhibitors in Development: Vandetanib and Cediranib
9.8 References
Part III: Cardiovascular and Metabolic Diseases
Chapter 10: Sitagliptin (Januvia): A Treatment for Type 2 Diabetes
10.1 Background
10.2 Pharmacology
10.3 Structure–Activity Relationship (SAR)
10.4 Pharmacokinetics and Drug Metabolism
10.5 Efficacy and Safety
10.6 Syntheses
10.7 References
Chapter 11: Aliskiren (Tekturna), The First-in-Class Renin Inhibitor for Hypertension
11.1 Background
11.2 Pharmacology
11.3 Structure–Activity Relationship (SAR)
11.4 Pharmacokinetics and Drug Metabolism
11.5 Efficacy and Safety
11.6 Syntheses
11.7 References
Chapter 12: Vernakalant (Kynapid): An Investigational Drug for the Treatment of Atrial Fibrillation
12.1 Background
12.2 Pharmacology
12.3 Structure–Activity Relationship (SAR)
12.4 Pharmacokinetics and Drug Metabolism
12.5 Efficacy and Safety
12.6 Synthesis
12.7 References
Chapter 13: Conivaptan (Vaprisol): Vasopressin V1a and V2 Antagonist for Hyponatremia
13.1 Background
13.2 Pharmacology
13.3 Structure–Activity Relationship (SAR)
13.4 Pharmacokinetics and Drug Metabolism
13.5 Efficacy and Safety
13.6 Syntheses
13.7 References
Chapter 14: Rivaroxaban (Xarelto): A Factor Xa Inhibitor for the Treatment of Thrombotic Events
14.1 Background
14.2 Pharmacology
14.3 Structure–Activity Relationship (SAR)
14.4 Pharmacokinetics and Drug Metabolism
14.5 Efficacy and Safety
14.6 Synthesis
14.7. Compounds in Development: Apixaban and Otamixaban
14.8 References
Chapter 15: Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension
15.1 Background
15.2 Treatment of PAH
15.3 Endothelin Antagonists
15.4 Synthesis of Bosentan
15.5 Synthesis of Sitaxsentan
15.6 Synthesis of Ambrisentan
15.7 Conclusion
15.8 References
Part IV: Central Nervous System Diseases
Chapter 16: Varenicline (Chantix): An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
16.1 Background
16.2 Discovery Chemistry Program
16.3 Pharmacology
16.4 Pharmacokinetics and Drug Metabolism
16.5 Efficacy and Safety
16.6 Syntheses
Acknowledgments
16.7 References
Chapter 17: Donepezil, Rivastigmine and Galantamine: Cholinesterase Inhibitors for Alzheimer’s Disease
17.1 Background
17.2 Pharmacology
17.3 Structure-Activity Relationship (SAR)
17.4 Pharmacokinetics and Drug Metabolism
17.5 Efficacy and Safety
17.6 Syntheses of Donepezil
17.7 Syntheses of Rivastigmine
17.8 Syntheses of Galantamine
17.9 References
Chapter 18: Aprepitant (Emend): A NK1 Receptor Antagonist for the Treatment of Postchemotherapy Emesis
18.1 Background
18.2 In Vitro Pharmacology and Structure-Activity Relationships (SAR)
18.3 In Vivo Pharmacology
18.4 Pharmacokinetics and Drug Metabolism
18.5 Efficacy and Safety
18.6 Synthesis of Aprepitant (1) and Fosaprepitant (21)
18.7 References
Chapter 19: Armodafinil (Nuvigil): A Psychostimulant for the Treatment of Narcolepsy
19.1 Background
19.2 Pharmacology
19.3 Pharmacokinetics and Drug Metabolism
19.4 Efficacy and Safety
19.5 Synthesis
19.6 References
Part V: Miscellaneous
Chapter 20: Raloxifene, Evista: A Selective Estrogen Receptor Modulator (SERM)
20.1 Background
20.2 Mechanism of Action
20.3 Pharmacokinetics and Drug Metabolism
20.4 Efficacy and Safety
20.5 Syntheses
20.6 References
Chapter 21: Latanoprost (Xalatan): A Prostanoid FP Agonist for Glaucoma
21.1 Introduction
21.2 Syntheses
21.3 References
Index
Modern Drug Synthesis
Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.
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Library of Congress Calaloging-in-Publication Data:
Modern drug synthesis / edited by Jie Jack Li, Douglas S. Johnson.p. cm.Includes index.ISBN 978-0-470-52583-8 (cloth)1. Drugs—Design. 2. Pharmaceutical chemistry. I. Li, Jie Jack. II. Johnson, Douglas S. (Douglas Scott), 1968-RS420.M6325 2010615′.19—dc222010007983
Preface
Our first two books on drug synthesis, Contemporary Drug Synthesis and The Art of Drug Synthesis, were published in 2004 and 2007, respectively. They have been warmly received by the chemistry community. Here is our third installment in the Drug Synthesis series.
This book has five sections. Section I, “Infectious Diseases” covers three drugs; Section II, “Cancer” reviews five drugs, three of which are kinase inhibitors; Section III covers eight drugs that target cardiovascular and metabolic diseases; Section IV on central nervous system diseases concerns four classes of recent drugs; and Section V summarizes two drugs: raloxifene hydrochloride (Evista) for the treatment of osteoporosis and latanoprost (Xalatan) for ophthalmological indications.
In this installment of the drug synthesis series, we have placed more emphasis on other aspects of medicinal chemistry in addition to the synthesis. To that end, each chapter is divided into seven sections:
We are indebted to the contributing authors from both industry and academia. Many of them are veterans in medicinal chemistry. Some of them discovered the drugs that they reviewed. As a consequence, their work tremendously elevated the quality of this book. Meanwhile, we welcome your critique and suggestions so we can make this drug synthesis series even more useful to the medicinal/organic chemistry community.
Jack Li and Doug JohnsonFebruary 1, 2010
Contributors
Dr. Joseph D. Armstrong III Department of Process Research Merck & Co. Inc. PO Box 2000 Rahway, NJ 07065
Dr. Frank R. Busch Pharmaceutical Sciences Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Victor J. Cee Amgen, Inc. Mailstop 29-1-B 1 Amgen Center Dr. Thousand Oaks, CA 91320
Dr. Jotham W. Coe Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Jason Crawford Centre for Drug Research & Development 364-2259 Lower Mall University of British Columbia Vancouver, BC, Canada V6T 1Z4
Dr. David J. Edmonds Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Scott D. Edmondson Medicinal Chemistry Merck & Co. Inc. PO Box 2000 Rahway, NJ 07065
Prof. Arun K. Ghosh Departments of Chemistry and Medicinal Chemistry Purdue University 560 Oval Drive West Lafayette, IN 47907
Dr. David L. Gray CNS Medicinal Chemistry Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Benjamin S. Greener Pfizer Global Research and Development Sandwich Laboratories Ramsgate Rd. Sandwich, Kent, UK, CT13 9NJ
Dr. Kevin E. Henegar Pharmaceutical Sciences Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. R. Jason Herr Medicinal Chemistry Albany Molecular Research, Inc. 26 Corporate Cir. PO Box 15098 Albany, NY 12212-5098
Dr. Shuanghua Hu Discovery Chemistry Bristol-Myers Squibb Co. 5 Research Parkway Wallingford, CT 06492
Yazhong Huang Discovery Chemistry Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492
Dr. Julianne A. Hunt Franchise and Portfolio Management Merck & Co., Inc. Rahway, NJ 07065
Kapil Karki Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Brian A. Lanman Amgen, Inc. Mailstop 29-1-B 1 Amgen Center Drive Thousand Oaks, CA 91320
Dr. Jie Jack Li Discovery Chemistry Bristol-Myers Squibb Co. 5 Research Parkway Wallingford, CT 06492
Dr. John A. Lowe, III JL3Pharma LLC 28 Coveside Ln. Stonington CT 06378
Cuthbert D. Martyr Department of Chemistry Purdue University 560 Oval Drive West Lafayette, IN 47907
Dr. David S. Millan Pfizer Global Research and Development Sandwich Laboratories Ramsgate Rd. Sandwich, Kent, UK, CT13 9NJ
Dr. Sajiv K. Nair Pfizer Global Research and Development 10770 Science Center Dr. La Jolla, CA92121
Dr. Martin Pettersson Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Marta Piñeiro-Núñez Eli Lilly and Co. Lilly Corporate Center Indianapolis, IN 46285
Dr. David Price Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Subas Sakya Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Robert A. Singer Pharmaceutical Sciences Pfizer Global Research and Development Eastern Point Rd. Groton, CT 06340
Dr. Jennifer A. Van camp Hit to Lead Chemistry Global Pharmaceutical R&D Abbott Laboratories 200 Abbott Park Rd. Dept. R4CW, Bldg. AP52N/1177 Abbott Park, IL 60064-6217
Dr. Feng Xu Department of Process Research Merck & Co. Inc. PO Box 2000 Rahway, NJ 07065
Dr. Ji Zhang Process Research and Development Bristol-Myers Squibb Co. 1 Squibb Dr. New Brunswick, NJ 08903
PART I
INFECTIOUS DISEASES
Chapter 1
Raltegravir (Isentress): The First-in-Class HIV-1 Integrase Inhibitor
Julianne A. Hunt
1.1 Background
HIV/AIDS is a global pandemic. Nearly three decades of HIV/AIDS research has resulted in the development of more than 20 antiretroviral drugs approved by the U.S. Food and Drug Administration (FDA) for treatment of the disease; combinations of these drugs, known as highly active antiretroviral therapies (HAART), have dramatically decreased morbidity and increased life expectancy.1 Nevertheless, HIV/AIDS remains a significant cause of morbidity and mortality worldwide. The Joint United Nations Program on HIV/AIDS estimated in 2007 that more than 33 million people lived with the disease worldwide and that AIDS killed more than 2 million people, including 330,000 children. In the United States alone, the Centers for Disease Control and Prevention (CDC) estimated in 2006 that more than one million people were living with HIV infection.2–4 Although antiretroviral drugs have undeniably changed the lives of many HIV-positive individuals, an unmet medical need clearly exists.
Raltegravir, or Isentress (1), is the first FDA-approved inhibitor of HIV integrase. HIV/AIDS drugs are categorized according to their mode of action as nucleoside and nucleotide reverse transcriptase inhibitors [NRTIs, e.g., tenofovir (2)], nonnucleotide reverse transcriptase inhibitors [NNRTIs, e.g., efavirenz (3)] protease inhibitors [PIs, e.g., ritonavir (4)], fusion inhibitors [e.g., enfuvirtide (5)], entry inhibitors [e.g., the CCR5 antagonist maraviroc (6)], and integrase inhibitors (INSTIs, e.g., raltegravir).
Until recently, all FDA-approved drugs for HIV/AIDS treatment targeted either the viral reverse transcriptase (RT) or protease (PR) enzymes, and treatment guidelines specified that HAART multidrug cocktails should comprise one NNRTI or one PI in combination with two NRTIs.5 Two of the most significant limitations on the effectiveness of these HAART combinations have been drug-related toxicities and the emergence of resistant viruses.6 Drugs with novel modes of action—such as viral entry inhibitors and integrase (IN) inhibitors—have been sought to offer antiretroviral treatment-experienced HIV patients who harbor a drug-resistant virus or suffer toxicities with HAART an opportunity to achieve immunologic recovery and virologic suppression. IN inhibitors have been of particular interest to HIV/AIDS researchers because, unlike RT and PR, IN has no human homolog, and thus inhibitors of IN might be better tolerated at high doses.7
Raltegravir (1) is the first commercially available antiretroviral agent to target IN; at present, it is the only IN inhibitor approved for clinical use. Launched in 2007, raltegravir was originally indicated for combination therapy with other antiretroviral agents in treatment-experienced adults with evidence of viral replication and multidrug-resistant HIV-1 strains. In July 2009, the FDA approved an expanded indication for raltegravir to include treatment-naive adult patients, and in December 2009, the U.S. Department of Health and Human Services (DHHS) revised its HIV treatment guidelines to add a raltegravir combination to the preferred regimens for treatment-naive HIV patients.5 In this chapter, the pharmacological profile and chemical syntheses of raltegravir will be described in detail.
1.2 Pharmacology
The HIV-1 replication cycle involves three key viral enzymes, all of which represent targets for antiretroviral drugs: RT, PR, and IN. RT and PR inhibitors are well represented in the HIV/AIDS treatment armamentarium, but until recently, inhibition of IN had not been successfully exploited in the clinic, despite nearly 20 years of intensive research.8
The enzymatic mechanisms of IN have been extensively reviewed.9 IN catalyzes the insertion of viral genetic material into human DNA through a multistep process that includes 3’-processing, (removal of the terminal dinucleotide from each 3’-end of the viral DNA) and strand transfer (joining of the viral DNA to the host DNA). Both 3’-processing and strand transfer are catalyzed by a triad of acidic residues, D64, D116, and E152, that bind divalent metals such as Mg2+. Divalent metals are required for 3’-processing and strand transfer and also for the assembly of the preintegration complex, which allows viral genetic material to cross the host nuclear membrane and access the host genome.
1.3 Structure–Activity Relationship (SAR)
The 4-aryl-2,4-diketobutanoic acid class of IN inhibitors (also known as 1,3-diketo acids, or DKAs) was discovered independently by researchers from Merck and Shionogi, with patents from both groups published in the same year.13 From a random screen of > 250,000 compounds, the Merck group identified DKAs as the most active IN inhibitors. Compound 7 was the most potent compound found in this screen (Table 1), completely inhibiting HIV-1 infection in a cell-based assay at a concentration of 10 μM.10
Table 1. Activity of DKAs and Related Structures against HIV-1 Integrase
Entry
1
1
0.01
2
0.08
3
0.65
4
0.02
5
0.04
6
0.01
7
0.08
8
0.007
The Shionogi group’s first patent13d described compounds (e.g., 8) in which an isosteric tetrazole replaced the carboxylic acid group in the critical but biologically labile DKA pharmacophore. Compound 8, also known as 5CITEP, inhibited HIV-1 3’-processing as well as strand-transfer activity,14 and was the first inhibitor co-crystallized with IN.15 A subsequent patent from the Shionogi group described the systematic modification of the 5CITEP framework to include a variety of heterocyclic replacements for the indole and tetrazole moieties, culminating in the first clinically tested HIV-1 IN inhibitor, compound 9, also known as S-1360.16,17 Clinical development of S-1360, undertaken by a Shionogi–GSK joint venture, was halted when the compound failed in efficacy studies in humans (due to formation of an inactive metabolite via reduction at the carbon adjacent to the triazole).18
The Merck group’s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[1,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound.
Concurrent with the Merck group’s efforts to find an IN inhibitor that would be successful in the clinic, a separate Merck group working on inhibitors of HCV polymerase discovered that dihydroxypyrimidine carboxamide 12 (which, like the other compounds shown in Table 1, evolved from DKA lead structures) was a potent inhibitor of HIV-1 strand transfer, but completely inactive against HCV polymerase.22 Modification of the dihydroxypyrimidine core to the corresponding N-methylpyrimidinone23 followed by optimization of the N-methylpyrimidinone series with respect to metabolic stability, pharmacokinetic profile, antiviral activity, and genotoxicity led to the identification of raltegravir, the first IN inhibitor to be approved by the FDA.12
A second IN inhibitor has reached Phase III clinical trials since the launch of raltegravir. Elvitegravir (13) is a dihydroquinolone carboxylic acid; the monoketo acid motif of this series of inhibitors is proposed to mimic the keto-enol-acid triad of the DKA lead structures.24 Like raltegravir, elvitegravir is a specific inhibitor of HIV-1 strand transfer.25
1.4 Pharmacokinetics and Drug Metabolism
The plasma half-life of raltegravir (1) in rats was 7.5 h and in dogs was 13 h. Plasma half-life was biphasic in both species, with a short initial (α) phase and a prolonged terminal (β) phase. The major route of metabolism for raltegravir was glucuronidation; the glucoronide was shown to be the conjugate of the hydroxyl group at C5 of the pyrimidinone ring.12
In humans, the pharmacokinetics of raltegravir was studied in both healthy HIV-negative subjects and in HIV-infected patients. In healthy HIV-negative subjects, raltegravir was rapidly absorbed; as was seen in preclinical species, concentrations declined from the mean maximum plasma concentration (Cmax) in a biphasic manner, with an apparent half-life of approximately 1 h for the α phase and an apparent half-life of 7–12 h for the β phase. Raltegravir was generally well tolerated at doses of up to 1600 mg/day for 10 days. The mean plasma concentration of raltegravir at the end of a 12-h dose administration interval exceeded 33 nM (the in vitro IC95 in 50% human serum) after multiple doses ≥ 100 mg, supporting twice-daily dosing with doses ≥ 100 mg.26
In a double-blind, placebo-controlled, dose-ranging study in 35 antiretroviral-naive HIV-infected patients (Protocol 004), subjects were randomized to receive placebo or one of four raltegravir doses (100, 200, 400, or 600 mg) twice daily over 10 days. Although dose proportionality was not observed (possibly due to intersubject variability and the small number of patients), the pharmacokinetic data gathered in this study supported the selection of a 400-mg dose for raltegravir.27
While the NRTIs, NNRTIs, and PIs are primarily metabolized in humans via cytochrome P450 (CYP450), raltegravir is neither a substrate nor an inhibitor of CYP450 nor is it an inducer of CYP3A4, indicating that drug–drug interactions with drugs metabolized by CYP450 are unlikely. Instead, raltegravir is primarily metabolized via uridine diphosphate glucoronosyl transferase 1A1 (UGT1A1).28
1.5 Efficacy and Safety
Raltegravir (1) is a potent inhibitor of HIV integrase, originally approved for combination therapy with other antiretroviral agents in treatment-experienced adults with evidence of viral replication and multidrug-resistant HIV-1 strains, and recently (July 2009) approved for combination therapy with other antiretroviral agents in treatment-naive adult patients. Raltegravir is dosed orally twice daily (400 mg); no dose adjustment is required when it is co-administered with other antiretroviral agents.
Phase II clinical trials with raltegravir were conducted in both treatment-naive (Protocol 004) and treatment-experienced (Protocol 005) HIV patients. In Protocol 004, 201 treatment-naive HIV patients received either raltegravir or efavirenz (3, the current gold standard for treatment-naive patients) for 48 weeks on a background of tenofovir (2) and lamivudine combination therapy. Similar proportions of patients in the raltegravir and efavirenz groups achieved an HIV RNA level of < 50 copies/mL.29 In Protocol 005, 179 treatment-experienced HIV patients with viral resistance received either raltegravir or placebo in combination with optimized background therapy (OBT) chosen by the investigator. In the raltegravir group, 57–67% of patients achieved an HIV RNA level of < 50 copies/mL, compared with 14% in the placebo group.30
In the two Phase III BENCHMRK clinical trials, 699 treatment-experienced patients with triple-class resistant HIV were randomized to receive either raltegravir (400 mg p.o., b.i.d.) plus OBT or OBT alone. In both trials, patients in the raltegravir group improved both virological (HIV RNA level < 50 copies/mL) and immunological (increased CD4+ cell counts) outcomes compared to patients in the placebo group.31 In the Phase III STARTMRK study, 563 treatment-naive patients were randomized to receive either raltegravir (400 mg) or efavirenz (600 mg) in combination with tenofovir and emtricitabine. Analysis of the 48-week results showed that raltegravir-based combination treatment was noninferior to efavirenz-based combination treatment; this study was the basis for the expansion of approved indications for raltegravir to include treatment-naive patients.32 Recently, analysis of the 96-week results for STARTMRK confirmed the findings from the 48-week analysis.33 Finally, 96-week results for Protocol 004 treatment-naive patients confirmed that the raltegravir group continued to show a suppression of viral replication comparable to that shown by the efavirenz group.34
The most commonly reported adverse events of moderate or severe intensity that occurred in > 2% of patients treated with raltegravir were headache, nausea, asthenia/weakness, and fatigue. It is interesting that the STARTMRK study showed that patients on raltegravir-based combination treatment showed significantly less impact on lipid levels than patients on efavirenz-based combination treatment.32,33
1.6 Syntheses
The discovery synthesis of raltegravir,12 started from nitrile 14, which was converted to the corresponding amidoxime 15. Reaction of 15 with dimethylacetylenedicarboxylate provided the dihydroxypyrimidine core (16)35 of raltegravir. Benzoylation followed by methylation provided the N-methylpyrimidone 17, with the O-methylated pyrimidine analog (not shown) as a minor product. The discovery route to many analogs of raltegravir proceeded via subsequent installation of the fluorobenzylamide at C4 of the pyrimidone ring, followed by deprotection and functionalization at the C2 position. However, in the case of raltegravir, the preferred route (due to scalability of the purification process) involved functionalization at the deprotected amine 18 to provide the oxadiazole amide at C2 followed by installation of the fluorobenzylamide at C4 to provide up to 10 g of 19, the free hydroxyl form of raltegravir. Conversion to the potassium salt with potassium hydroxide provided raltegravir potassium 1.
The process synthesis of raltegravir36 followed a convergent approach. Synthesis of the pyrimidone amine 22 started from 2-hydroxy-2-methylpropanenitrile, which was converted to the corresponding aminocyanohydrin with ammonia (30 psi, 10 °C, 97% yield), and then protected with benzylchlorofomate to provide Cbz-amine 14 in 88% yield. The process synthesis paralleled the discovery route from 14 through 15 to provide 16, with a somewhat improved yield (52%) for the dihydroxypyrimidine. Deprotonation of 16 with magnesium methoxide followed by treatment with methyl iodide provided the N-methylpyrimidone 20 with < 0.5% of the O-methylpyrimidine side product. Installation of the fluorobenzylamide was accomplished by heating in ethanol followed by crystallization to provide 21, and hydrogenolysis of the Cbz-protected amine provided amine 22. Synthesis of the oxadiazole 23 began with the reaction of methyltetrazole with ethyl oxalyl chloride to provide the ethyl oxalyltetrazole intermediate, which rearranged with loss of nitrogen on heating in toluene. The crude ethyl ester was saponified with potassium hydroxide to give the oxadiazole carboxylate salt 23. Finally, reaction of the acid chloride of 23 (formed using oxalyl chloride) with amine 22 provided the free hydroxyl form of raltegravir, which was converted to raltegravir potassium 1 with potassium hydroxide.
In summary, raltegravir (1), which evolved from the DKA class of HIV integrase strand transfer inhibitors, is the first FDA-approved integrase inhibitor. The drug was originally indicated for combination therapy with other antiretroviral agents in treatment-experienced adults with evidence of viral replication and multidrug-resistant HIV-1 strains, but the FDA recently approved an expanded indication to include treatment-naive patients, and the DHHS has added a raltegravir combination to the list of preferred regimens for treatment-naive adult patients. Viral resistance to new HIV/AIDS drugs is inevitable, and, indeed, multiple viral amino acid mutations have been identified that confer resistance to raltegravir,37 necessitating a continuing search for improved HIV/AIDS therapies. However, the development of raltegravir, the first member of an entirely new class of drugs that target a viral mechanism not previously exploited in the clinic, has provided physicians and patients a welcome addition to the HIV/AIDS treatment armamentarium.
1.7 References
1. Mocroft, A.; Vella, S.; Benfiedl, T. L.; Chiesi, A.; Miller, V.; Gargalianos, P.; d’Arminio Monforte, A.; Yust, I.; Bruun, J. N.; Phillips, A. N.; Lundgren, J. D. Lancet, 1998, 353, 1725–1730.
2. Kallings, L. O. J. Intern. Med.2008, 263, 218–243.
3. UNAIDS “2007 AIDS Epidemic Update,” http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf; accessed 2009-11-15.
4. CDC, “New estimates of U.S. HIV Prevalence, 2006” http://www.cdc.gov/hiv/topics/surveillance/resources/factsheets/pdf/prevalence.pdf; accessed 2009-11-15.
5. Panel on Antiretroviral Guidelines for Adults and Adolescents. “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.” DHHS. December 1, 2009; 1–161.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf; accessed 2009-12-02.
6. Tozzi, V.; Zaccarelli, ML; Bonfigli, S.; Lorenzini, P.; Liuzzi, G.; Trotta, M. P.; Forbici, F.; Gori, C.; Bertoli, A.; Bellagamba, R.; Narciso, P.; Perno, C. F.; Antinori, A. Antivir. Ther.2006, 11, 553–560.
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11. (a) Espeseth, A. S.; Felock P.; Wolfe, A.; Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J. Y.; Young, S.; Hamill, T.; Cole, J. L.; Hazuda, D. J. Proc. Natl. Acad. Sci. USA.2000, 97, 11244–11249. (b) Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A. S.; Wolfe, A.; Egbertson, M.; Bourgeois, M.; Melamed, J.; Wai, J. S.; Young, S.; Vacca, J.; Hazuda, D. J.; Proc. Natl. Acad. Sci. USA.2002, 99, 6661–6666.
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20. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai, J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P. Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.; Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong, B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.; Holloway, M. K.; Young, S. D. Proc. Natl. Acad. Sci. USA2004, 101, 11233–11238.
21. Little, S.; Drusano, G.; Schooley, R. Paper presented at 12th Conference on Retroviruses and Opportunistic Infections, Feb. 22–25, 2005, Boston, U.S.A.
22. Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.; Muraglia, E.; Rowley, M.; Paz, O. G.; Laufer, R.; Monteagudo, E.; Pace, P. J. Med. Chem.2006, 49, 6646–6649.
23. Gardelli, C.; Nizi, E.; Muraglia, E.; Crescenzi, B.; Ferrarra, M.; Orvieto, F.; Pace, P.; Pescatore, G.; Poma, M.; Rico Ferreira, M. R.; Scarpelli, R.; Hommick, C. F.; Ikemoto, N.; Alfieri, A.; Verdirame, M.; Bonelli, F.; Gonzalez Paz, O.; Monteagudo, E.; Taliani, M.; Pesci, S.; Laufer, R.; Felock, P.; Stillmock, K. A.; Hazuda, D.; Rowley, M.; Summa, V. J. Med. Chem.2007, 50, 4953–4975.
24. (a) Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai, H. J. Med. Chem.2006, 49, 1506–1506. (b) Sato, M.; Kawakami, H.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Matsuzaki, Y.; Yamataka, K.; Ikeda, S.; Shinkai, H. J. Med. Chem.2009, 52, 4869–4882.
25. DeJesus, E.; Berger, D.; Markowitz, M.; Cohen, C.; Hawkins, T.; Ruane, P.; Elion, R.; Farthring, C.; Zhong, L.; Chen, A. K.; McColl, D.; Kearney, B. P. J. Acquir. Immune Defic. Syndr.2006, 43, 1–5.
26. Iwamoto, M.; Wenning, L. A.; Petry, A. S.; Laethem, M.; De Smet, M.; Kost, J. T.; Merschman, S. A.; Strohmaier, K. M.; Ramael, S.; Lasseter, K. C.; Stone, J. A.; Gottesdiener, K. M.; Wagner, J. A. Clin. Pharmacol. Ther.2008, 83, 293–299.
27. Markowitz, M.; Morales-Ramirez, J. O.; Nguyen, B.-Y.; Kovacs, C. M.; Steigbigel, R. T.; Cooper, D. A.; Liporace, R.; Schwartz, R.; Isaacs, R.; Gilde, L. R.; Wenning, L.; Zhao, J.; Teppler, H. J. Acquir. Immune Defic. Syndr.2006, 43, 509–515. [Erratum J. Acquir. Immune Defic. Syndr.2007, 44, 492.]
28. Kassahun, K.; McIntosh, I.; Cui, D.; Hreniuk, D.; Merschman, S.; Lasseter, K.; Azrolan, N.; Iwamoto, M.; Wagner, J. A.; Wenning, L. A. Drug Metab. Dispos.2007, 35, 1657–1663.
29. Markowitz, M.; Nguyen, B. Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J. O.; Crumpacker, C. S.; Isaacs, R. D.; Gilde, L. R.; Wan, H.; Miller, M. D.; Wenning, L. A.; Teppler, H. J. Acquir. Immune Defic. Syndr.2007, 46, 125–133.
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34. Markowitz, M.; Nguyen, B.-Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J. O.; Crumpacker, C. S.; Isaacs, R. D.; Campbell, H.; Strohmaier, K. M.; Wan, H.; Danovich, R. M.; Teppler, H. J. Acquir. Immune Defic. Syndr.2009, 52, 350–356.
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Chapter 2
Maraviroc (Selzentry): The First-in-Class CCR5 Antagonist for the Treatment of HIV
David Price
2.1 Background
Infection with HIV leads, in the vast majority of cases, to progressive disease and ultimately death. By 2004, just 23 years after AIDS was first recognized, the Joint United Nations Programme on HIV/AIDS estimated that 42 million people worldwide were infected with HIV, with more than 20 million dead since the beginning of the epidemic. Furthermore, rates of infection are once again on the increase in the developed world.1 Despite the undoubted achievements of highly active antiretroviral therapy (HAART) using cocktails of reverse transcriptase and protease inhibitors,2 there is still a high unmet medical need for better tolerated, conveniently administered agents to treat HIV and AIDS.3,4
HIV enters the host cell by fusing the lipid membrane of the virus with the host cell membrane. This fusion is triggered by the interaction of proteins on the surface of the HIV envelope with specific cell surface receptors. One of these is CD4, the main receptor for HIV-1 that binds to gp120, a surface protein on the virus particle.5 CD4 alone, however, is not sufficient to permit HIV fusion and cell entry–an additional co-receptor from the chemokine family of G-protein coupled receptors (GPCRs) is required. The chemokine receptor CCR5 has been demonstrated to be the major co-receptor for the fusion and entry of macrophage tropic (R5-tropic) HIV-1 into cells. R5-tropic strains are prevalent in the early asymptomatic stages of infection. Shifts in tropism do occur during progression, mainly to X4 viruses that use CXCR4 as co-receptor, however, approximately 50% of individuals are infected with strains that maintain their requirement for CCR5. There is evidence that homozygotes possessing a 32-base pair deletion in the CCR5 coding region are resistant to infection with R5-tropic HIV-1. These homozygotes do not express functional CCR5 receptors on the cell surface. Individuals who are heterozygous for the 32-base pair deletion display significantly longer progression times to the symptomatic stages of infection and evidence is emerging that they respond better to HAART. Moreover, CCR5-deficient individuals are apparently fully immunocompetent, indicating that absence of CCR5 function may not be detrimental and that a CCR5 antagonist should be well tolerated. New mechanisms of action are particularly attractive to avoid issues of viral resistance and CCR5 antagonists have been an intense area of research within the HIV arena over the last decade with a number of compounds progressing to clinical trials from differing research institutions.6–8
Ancriviroc (2) was the first CCR5 antagonist to advance to clinical studies, where it was safe and demonstrated a clear antiviral effect, although cardiac side effects (QT prolongation) were noted at the highest dose tested (400 mg twice daily). It is of interest that the discovery and development timelines of CCR5 antagonists within various research groups mirrors the increased interest and understanding in hERG pharmacology, and often the two areas are closely intertwined.9 Indeed concerns around the cardiac liabilities that may be attributed to off-target pharmacology (whether mediated through hERG or other pharmacologies) has complicated and stopped the development of a number of CCR5 antagonists in the clinic. A high therapeutic index is particularly important in the HIV arena as drugs to treat HIV are rarely given in isolation, rather in combination with other agents to prevent emergence of viral resistance. Many of the agents that a CCR5 antagonist could be co-administered with have known interactions with cytochrome P450 enzymes that may affect circulating levels of other compounds in the treatment regime. This information, combined with the need to maintain a free plasma concentration of the CCR5 antagonist above the antiviral IC90 drives the need for a large safety window. Thus achieving high selectivity with respect to hERG affinity to avoid cardiac liabilities was a key objective for the project from the outset. Further safety concerns surfaced in the development of aplaviroc (4) with the occurrence of severe hepatotoxicity in several patients leading to the stopping of any further studies in October 2005. This finding has lead to concerns about possible class-specific long-term adverse effects of CCR5 antagonists, particularly regarding hepatotoxicity or malignancy. Maraviroc (1) and aplaviroc (4) were proceeding through development at approximately the same time and with the halting of aplaviroc, there was high scrutiny of the safety profile of maraviroc from the clinical data. Post-analysis, it was decided that there was sufficient confidence in the profile of maraviroc to warrant the approval of the agent, and maraviroc was launched in 2007. The clinical history of vicriviroc (3) has been complicated, and it would appear the compound is currently in Phase 3, with an estimated completion date of the studies in 2011.
2.2 Structure–Activity Relationship (SAR)
The SAR around maraviroc (1) has been extensively reported, in particular the tactics used to successfully deliver a compound with a maximum therapeutic window over QT prolongation (Tables 1 and 2).6,9 The validation and utility of a high-throughput binding assay for the hERG ion channel was an essential component of the drug discovery process. The design of synthetic routes to enable the late-stage variation of differing structural elements is a key skill in the drug discovery process, in particular ensuring that there are large monomer pools available for the final reaction to allow a large coverage of chemical space. The design criteria for selection of acid monomers was strict in terms of physicochemical properties of the final products (log D range 1.5–2.3), so that compounds prepared would have the best chance of possessing good pharmacokinetic and biopharmaceutical properties. This log D range was decided on from analysis of previous compounds prepared within the project as being most appropriate. In terms of the structural features of the monomers used as diverse a range as possible was selected to identify possible deleterious interactions with the hERG channel (Table 2).
Table 1. Antiviral Activity and hERG Channel Activity for Key Heterocyclic Compounds
Table 2. Antiviral Activity and hERG Channel Activity for Key Triazole Compounds
Ring homologation of 5 (log D 1.6) to compound 9 (log D 2.1) immediately gave an indication that an increase in antiviral activity was possible with a small decrease in affinity for the hERG channel (Table 2). This reduction is presumably due to some deleterious steric clash with residues in the ion channel with the increased size of the cyclopentyl substituent. This result also confirmed that key structural elements could reduce hERG affinity regardless of an increase in overall lipophilicity. Compound 10 (log D 1.8) also showed a small decrease in affinity for the hERG channel compared to the lead 5, and this suggested that there could be a further reduction in affinity for hERG by fluorination of the amide substituent. Combining the data from 9 and 10 lead to the design and synthesis of the 4,4-difluorocyclohexyl group of maraviroc 1 (log D 2.1), which possessed no binding to the hERG channel when screened at 300 nM. The level of antiviral potency displayed was outstanding with a nanomolar IC90. Within the triazole series the 4,4-difluorocyclohexyl group is unique in its antiviral profile and lack of affinity for the hERG channel. The 4,4-difluorocyclohexyl group is clearly not tolerated within the ion channel due to the steric demands of the cyclohexyl group and also the dipole generated by the difluoro moiety. Maraviroc also possessed high aqueous solubility (> 1 mg/mL across the pH range) and could be crystallized as the free base or the besylate salt. The early identification and optimization of stable crystalline polymorphs of maraviroc was a key contribution to the rapid development timelines and the importance of strong biopharmaceutical properties should not be underestimated.
2.3 Pharmacokinetics and Safety
In preclinical studies maraviroc (1) showed no significant activity against a range of pharmacologically relevant enzymes, ion channels; and receptors up to 10 μM, as measured in binding competition and functional assays. It was also well tolerated in mouse and rat studies, with no significant effects on the central, peripheral, renal, or respiratory systems. Further profiling for cardiac effects and in particular those mediated via hERG showed only very weak affinity using whole-cell voltage clamp techniques with 19% inhibition at 10 μM, In canine isolated Purkinje fiber assays, maraviroc was devoid of any effects at 1 μM on action potential morphology. Upon progression into in vivo cardiovascular assessment, there were no biologically relevant or statistically significant haemodynamic or ECG changes in conscious freely moving dogs at free plasma levels > 100-fold the antiviral IC90 of maraviroc.
Maraviroc is rapidly absorbed after oral administration and plasma Tmax was achieved within 0.5–4.0 h post dose; steady-state plasma concentrations were achieved after 7 days of consecutive dosing. Maraviroc was metabolized by CYP3A4, although there is also a component of renal clearance of unchanged drug. As a CYP3A4 substrate, drug levels of maraviroc decrease when co-administered with strong CYP3A4 inducers and increase when administered with CYP3A4 inhibitors. Over the lower dose range studied (3–1200 mg) the pharmacokinetics were nonproportional; however, at clinically relevant doses, this was not significant. Maraviroc was a substrate for the transporter P-glycoprotein (Pgp) which is thought to limit the gut absorption of many compounds. At low intestinal concentrations of maraviroc, Pgp mediates efflux of maraviroc back into the lumen of the small intestine, thereby limiting the absorption of maraviroc. As the dose of maraviroc increases and concentrations in the gut lumen increase Pgp efflux may become saturated and so reduce the ability of Pgp to limit oral bioavailability. At doses up to 900 mg maraviroc was well tolerated, with postural hypotension being the dose-limiting effect. No clinically significant increases in QT prolongation were noted at relevant doses. Maraviroc does not modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. This is very important as maraviroc is co-administered with other antiviral agents and so does not effect the CYP-mediated clearance of other agents.
2.4 Syntheses
Maraviroc (1) can be simply disconnected into the 4,4-difluorocyclohexyl carboxylic acid (11), the phenpropyl linker 12 and the tropane triazole motif 13. Once these individual fragments have been prepared, it is relatively straightforward to link them together to complete the synthesis of maraviroc. The ordering of the steps to link the fragments together can be altered to minimize purification issues and ensure cost of goods (CoG) is not a hindrance. A comparison of the routes used by the discovery chemists that allowed them to investigate SAR relationships within the chemotype versus the route developed by the process chemists to deliver multikilogram quantities is a fascinating case history.
The initial synthesis of maraviroc that delivered material for preclinical studies has been published both in journals10,11 and in patent applications.12 It is to the credit of the discovery and development chemists that the large-scale routes are similar with the necessary improvements in yields and ease of operation on a large scale. The communication between the chemists in discovery and development was high, ensuring that the route used to deliver relatively small amounts of preclinical material could be adopted as the backbone of the development routes. Throughout the whole pharmaceutical industry, this close relationship between discovery and development is desired if delivery of bulk active pharmaceutical ingredient (API) is not going to be a rate limiting factor in development timelines.
Before engagement from the development chemistry community, the challenges facing the discovery synthesis group were optimization of robust conditions for the preparation of the triazole motif and the purification of 4,4-difluorocyclohexyl carboxylic acid before amide coupling in the final step. The triazole methodology at the time of initial synthesis required significant effort, and the starting material was commercially available N-benzyl tropinone (14). Oxime formation and single electron reduction furnished 16 with the required equatorially disposed primary amine. The amide 17 was prepared using the necessary acid chloride and Schotten–Baumann conditions. The iminoyl chloride was prepared by treatment of the amide 17 with phosphorous oxychloride, which could then be reacted with acetic hydrazide. Cyclization to the required triazole 18 was completed by heating under reflux in toluene with a catalytic quantity of p-toluene sulfonic acid. The benzyl protecting group could be removed by transfer hydrogenation to furnish the required intermediate 13. The triazole formation required significant optimization within the development phase. Even though the fundamental disconnection remained the same, modification of reagents and conditions were essential for the successful preparation of maraviroc. In particular, it was found that replacing phosphorous oxychloride with phosphorous pentachloride and minimizing the thermal instability of the intermediate iminoyl chloride before reaction with acetic hydrazide were critical to success.13,14
The use of fluorine in molecules of pharmacological interest is well known and there has been widespread research into methodologies for the introduction of this atom. Within the discovery synthesis of maraviroc, the initial preparation required the use of diethyl amino sulfur trifluoride (DAST), which is commercially available but does require careful handling due its well known thermal instability. Initial use of DAST for the fluorination of the ketone 19 gave an inseparable 1:1 mixture of the required difluoro compound 20 and the vinyl fluoride 21. The formation of vinyl fluoride co-products from the treatment of ketones with DAST is known in the literature and is difficult to control.
Optimization studies undertaken to influence the ratio of products, including temperature, reagent stoichiometry, and solvents were unsuccessful. It was decided that for early evaluation of maraviroc the use of DAST was acceptable. Within the discovery setting, the inseparable mixture of the difluoro and vinyl fluoro cyclohexyl esters 20 and 21 was subjected to Upjohn conditions for dihydroxylation of vinyl fluoro side product 21. After an overnight reaction, the required difluorocyclohexyl ester 20 could be isolated in high purity by flash column chromatography. Saponification gave the acid 11, which could be recrystallized from cyclohexane to furnish analytically pure material.
The aldehyde 25 was a key intermediate and could be prepared on scale from the commercially available ester 24 by partial reduction using DIBAL-H, this was a reaction where careful control of temperature was essential to prevent overreduction to the alcohol. With the aldehyde in hand, a simple reduction amination linked the two halves of maraviroc together for completion of the synthesis. Throughout the discovery phase of the project high-throughput chemistry was applied whenever possible to rapidly generate knowledge for the next design cycle. With this desire for the use of parallel chemistry, the reagent of choice for the final amide coupling was a polymer-bound carbodiimide reagent using dichloromethane as solvent. Once the amide coupling reaction was complete simple filtering through a pad of silica furnished maraviroc 1, which was recrystallized to analytical purity from toluene/hexane. It is interesting to note that alternative amide coupling reagents were investigated in the discovery laboratories; however, the polymer-bound reagent was the reagent of choice even on relatively large-scale reactions (up to 10 g) due to the ease of workup and the high purity of the product, which could be easily recrystallized to high purity. Alternative amide coupling reagents were investigated and rejected as the samples of maraviroc contained unacceptable impurity profiles for the studies required.
For large-scale development of maraviroc, the fluorination chemistry required modification due to concerns around safety, reproducibility of the DAST reaction, and the need for column chromatography to purify intermediates. The fluorination chemistry was eventually transferred to a specialist company who used the same starting material but was capable of using HF on large scale to produce intermediate 28. The starting material for the phenyl propyl linker was the commercially available β-amino ester 29, which was amidated in high yield. As the project progressed and large quantities of the ester 29 were needed, the material was delivered via an L-tartaric acid resolution of the racemic β-amino ester. A single-step partial reduction of the ester 30 to yield the required aldehyde 32 using DIBAL-H proved to be unsuccessful on larger scales, with overreduction to the alcohol 31 occurring under all conditions investigated. It was decided to follow this strategy, and by using sodium borohydride, it was possible to completely reduce the ester to the alcohol, which was then reoxidized to give the required aldehyde. Within the discovery and development routes, the same key reductive amination strategy was used to prepare maraviroc; however, the order of steps was modified, and the 4,4-difluorocyclohexyl group was introduced early in the synthesis. This was enabled by the now ready availability of the 4,4-difluorocyclohexyl carboxylic acid, so that this motif was no longer of such high value that it could be installed only in the final step, as in the discovery route.
In conclusion, the synthesis of maraviroc is a case history of the differing challenges faced by synthetic organic chemists working in the pharmaceutical industry. Within the discovery phase, the challenges were the rapid delivery of milligram quantities of compounds for screening using routes that allowed the generation of structure—activity relationships. Within the development phase, it was the delivery of a route capable of delivering kilogram quantities safely and in a cost-effective manner. The initial route used in the discovery of maraviroc was not trivial to transfer into the pilot plant and eventually into manufacturing facilities. Reagents and solvents needed to be replaced, impurities eliminated, and crystalline intermediates identified. It is to the credit of the creativity and imagination of the synthetic community that all these goals were achieved in a remarkably short period of time. Maraviroc was first prepared and screened in 2000 and was ultimately approved in 2007.16
2.5 References
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Chapter 3
Darunavir (Prezista): A HIV-1 Protease Inhibitor for Treatment of Multidrug-Resistant HIV
Arun K. Ghosh and Cuthbert D. Martyr
3.1 Background
Human immunodeficiency virus type 1 (HIV-1) infections continue to be a major global challenge in medicine in the 21st century. The World Health Organization (WHO) estimates that about 35 million people are living with HIV/AIDS (acquired immunodeficiency syndrome) with nearly 2.5 million new cases of HIV infection in 2008.1 These statistics indicate the magnitude of the global epidemic of HIV/AIDS today.
Early on, biochemical events critical to HIV replication revealed a number of important targets for therapeutic intervention of HIV/AIDS.2 Subsequently, drug development efforts in academic and industrial laboratories targeting retroviral enzymes, reverse transcriptase (RT), integrase (IN), and HIV protease (HIV-PR), led to the discovery of a variety of antiretroviral treatment regimens.3 Of particular interest, HIV-1 protease inhibitors (PIs) have proven to be highly effective in combination with reverse transcriptase inhibitors for the treatment of HIV/AIDS. Various approved PIs are shown in Figure 1. This combination therapy or highly active antiretroviral therapy (HAART) greatly improved the quality of life of HIV/AIDS patients, decreased mortality, and improved the course of HIV management in the United States and other industrialized nations.4
Figure 1. HIV protease inhibitors in order of FDA approval time up to 2005.
