Current Drug Synthesis E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley Series on Drug Synthesis
• Sprache: Englisch

Seitenzahl: 541

Veröffentlichungsjahr: 2022

Beschreibung

Current Drug Synthesis The latest entry in the widely read Drug Synthesis series In Current Drug Synthesis, accomplished medicinal chemist and researcher Dr. Jie Jack Li and 27 expert coauthors deliver an authoritative and comprehensive discussion of the medicinal chemistry of current drugs, as well as the cutting-edge science involved in their synthesis. The book demystifies the process of modern drug discovery for both industry practitioners and students, while capturing the state-of-the-art techniques used to discover some of the most impactful medicines on the market today. Covering six different disease areas - including infectious disease, cancer, cardiovascular and metabolic disease, the central nervous system, anti-inflammatory disease, and a miscellaneous section - the book explores 18 different drugs before concluding with chapters on computational drug discovery and peptide drugs. Each chapter includes coverage of background material on a relevant drug class or disease indication and key aspects of drug discovery, including structure-activity relationships, pharmacokinetics, drug metabolism, efficacy, and safety. Readers will also find: * Thorough introductions to drugs for infectious diseases, including relebactam, vaborbactam, and baloxavir marboxil * In-depth treatments of cancer-treating drugs, including darolutamide, venetoclax, and osimertinib * Comprehensive explorations of central nervous system drugs, including zuranolone and risdiplam * Extensive discussions of computational drug discovery and peptide drugs Perfect for medicinal, organic, synthetic, and process chemists, Current Drug Synthesis will also earn a place in the libraries of research scientists working in lead optimization and process development, as well as graduate students studying organic chemistry, heterocyclic chemistry, or medicinal chemistry.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Dedication

Preface

Contributing Authors

I: INFECTIOUS DISEASE DRUGS

1 Relebactam (Recarbrio), A β‐Lactamase Inhibitor for the Treatment of cIAI/cUTI/HABP/VABP

1. Background

2. Pharmacology

3. Structure–Activity Relationship (SAR)

4. Pharmacokinetics and Drug Metabolism

5. Efficacy and Safety

6. Syntheses

7. Summary

8. References

2 Vaborbactam (in Combination with Meropenem as Vabomere), a Non‐β‐Lactam β‐Lactamase Inhibitor for Treatment of Complicated Urinary Tract Infections and Pyelonephritis.

1 Background: Evolution from irreversible β‐lactam to irreversible non‐β‐lactam to reversible boron‐containing non‐β‐lactam β‐lactamase inhibitors

2 Discovery Medicinal Chemistry

3 Vaborbactam/Vabomere Clinical Trials

4 Vaborbactam Medicinal Chemistry Synthesis

5 Vaborbactam Process Chemistry Synthesis

6 Conclusions

7. References

3 Baloxavir Marboxil (Xofluza), A Cap‐Dependent Endonuclease Inhibitor for Treating Influenza

1 Background

2 Mechanism of Action

3 Structure–Activity Relationship

14,15

4 Pharmacokinetics and Drug Metabolism

22,23

5 Efficacy and Safety

23–27

6. Synthesis

28

7. Summary

8. References

4 Process Chemistry Development of the HIV Protease Inhibitor Drug Kaletra: A Mixture of Ritonavir and Lopinavir

1 Background:

2 Ritonavir Portion of Kaletra Syntheses

3 Discovery Synthesis of the Ritonavir Core

4 Discovery Synthesis of Ritonavir Wing Pieces

5 Large‐Scale Process Chemistry Synthesis of the Ritonavir Core

6 Large‐Scale Syntheses of the 5‐Hydroxymethyl Thiazole Wing Portion (16)

7 The Large‐Scale Coupling of the Thiazole Wing Pieces (17) and (19) to the Core (34)

8 Lopinavir (44) Portion of Kaletra—Discovery Synthesis and Process Development

9 Discovery Synthesis of Lopinavir

10 Discovery Synthesis of Wing Pieces (45) and (47)

11 Process Improvements to the Wing Pieces (45) and (47)

12 Optimization of Lopinavir Synthesis with Intermediates

13 Conclusions

14 References

5 Eravacycline (Xerava), A Novel and Completely Synthetic Fluorocycline Antibiotic

5.1 Background

5.2 Pharmacology

5.3 Structure–Activity Relationship (SAR)

5.4 Pharmacokinetics and Drug Metabolism

5.5 Efficacy and Safety

5.6 Synthesis

5.7. Summary

5.8 References

6 Albuvirtide (Aikening), A gp41 Analog as an HIV‐1 Fusion Inhibitor

1 Background

2 Pharmacology

3 Structure–Activity Relationship (SAR)

4 Pharmacokinetics and Drug Metabolism

5 Efficacy and Safety

6 Synthesis

7 Summary

8. References

II: CANCER DRUGS

7 Darolutamide (Nubeqa); An Androgen Receptor Antagonist for Treating Nonmetastatic, Castration‐Resistant Prostate Cancer

7.1 Background

7.2 Pharmacology

7.3 Structure–Activity Relationship (SAR)

7.4 Pharmacokinetics and Drug Metabolism

7.5 Efficacy and Safety

7.6 Synthesis

7.7 The Future

7.8 References

8 Venetoclax (Venclexta): A BCL‐2 Antagonist for Treating Chronic Lymphocytic Leukemia

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 Synthesis

8.7 Summary

8.8 References

9 Osimertinib (Tagrisso), A Potent and Selective Third‐Generation EGFR Inhibitor for the Treatment of Both Sensitizing and T790M‐Resistance Mutations

9.1 Background

9.2 Pharmacology

3 Structure–Activity Relationship (SAR)

9.4 Pharmacokinetics and Drug Metabolism

5 Efficacy and Safety

6 Synthesis

9.7 Summary

9.8. References

10 Sotorasib (LUMAKRAS), An Irreversible Covalent Inhibitor of KRAS

G12C

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. Summary

10.8 References

11 Lorlatinib (Lorbrena), An ALK Inhibitor for Treating NSCLC

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 Summary

11.8 References

12 Niraparib (Zejula), A Small Molecule, PARP1/2 Inhibitor for Treating Breast, Ovarian, and Pancreatic Cancers

12.1 Background

12.2 Pharmacology

12.3 Structure–Activity Relationship (SAR)

12.4 Pharmacokinetics and Drug Metabolism

12.5 Efficacy and Safety

6 Syntheses

12.7 Summary

12.8 References

13 Selinexor (Xpovio), An XPO1 Inhibitor and A New Class of Therapeutics for Treating Multiple Myeloma

13.1 Exportin1 (XPO1)

13.2 Overview of Multiple Myeloma

13.3 Development of Selinexor

13.4 Pharmacology and Mechanism

13.5 Pharmacokinetics, Pharmacodynamics and Drug Metabolism

13.6 Efficacy and Safety

13.7 Syntheses

13.8. Summary and Future

13.9. References

III: CNS DRUGS

14 Sage 217 (Zuranolone) for Treatment of Major Depressive Disorder

14.1 Background

14.2 Pharmacology

14.3 Structure–Activity Relationship (SAR)

14.4 Pharmacokinetics and Drug Metabolism

14.5 Efficacy and Safety

6 Synthesis

14.7 Summary

14.8 References

15 Risdiplam (Evrysdi), A Small Molecule,

SMN2

‐Directed RNA Splicing Modifier for Treating Spinal Muscular Atrophy

15.1 Background

15.2 Pharmacology

15.3 Structure–Activity Relationship (SAR)

15.4 Pharmacokinetics and Drug Metabolism

15.5 Efficacy and Safety

15.6 Syntheses

15.7 Summary

15.8 References

IV: MISCELLANEOUS DRUGS

16 Esaxerenone (Minnebro), An Oral, Non‐steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension

16.1 Background

16.2 Pharmacology

16.3 Structure–Activity Relationship (SAR)

16.4 Pharmacokinetics and Drug Metabolism

16.5 Efficacy and Safety

16.6 Syntheses

16.7 Summary

16.8 References

17 Voclosporin (Lupkynis), A Macrocyclic Peptide Inhibitor of Calcineurin for the Treatment of Lupus Nephritis

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

17.7 References

18 Computer‐Aided Drug Design

18.1 Background

18.2 Structure‐Based Drug Design (SBDD)

3 Ligand‐based Drug Design (LBDD)

4 Summary

5 References

Index

End User License Agreement

List of Tables

Chapter 1

Table 1 SAR of bridged bicyclic urea β‐lactamase inhibitors

Chapter 2

Table 1 Potentiation of Biapenem by compounds

28

.

Table 2 Potentiation of Cefepime by

RPX7009

(vaborbactam,

1

).

Chapter 3

Table 1 Timeline of influenza pandemics.

Table 2 Timeline of FDA‐approved antiviral drugs for influenza.

Chapter 5

Table 1. The structure–activity relationship of marketed tetracycline antibi...

Chapter 6

Table 1 Clinical trials summary

Table 2 Clinical trials secondary outcomes

Chapter 7

Table 1 FDA‐approved AR antagonists for prostate cancer

Table 2

In vitro

activity of darolutamide (

1

) derivatives

Table 3

In vitro

activity of darolutamide (

1

) derivatives.

Table 4

In vitro

activity of darolutamide (

1

) derivatives.

Table 5 Pharmacokinetic parameters of darolutamide (

1

),

12

and

13

.

Table 6 Clinical benefits for nmCRPC with approved 2nd‐generation AR antago...

Chapter 8

Table 1 Binding affinity of navitoclax (

9

) and ABT‐199 (

1

) for BCL‐2 protei...

Table 2 SAR for the substitution of terminal phenyl group on

10

.

Table 3 Acylsulfonamides lacking the P4‐binding “bent‐back” thiophenyl moie...

Chapter 9

Table 1 The optimization of lead compound

2

.

Table 2 Structures and selected properties of compounds

12

–

23

Chapter 10

Table 1 Covalent inhibitors of KRAS

G12C

Chapter 11

Table 1 Pharmacokinetic profiling of lorlatinib (

1

) in preclinical rat and d...

Table 2 Overall and intracranial objective response to lorlatinib (

1

) in ph...

Chapter 12

Table 1 PARPs (ARTD) as writers of post‐translational modification.

Table 2

In vitro

activity of Niraparib across PARP family.

Table 3

In vitro

activity of heterocyclic carboxamides.

Table 4

In vitro

activity of 3‐ and 4‐substituted phenyl on N2‐phenyl indaz...

Table 5

In vitro

activity of 4‐substituted phenyl on N2‐phenyl indazole carb...

Chapter 14

Table 1 Exploration of steroid core diverse substitution.

Table 2 Substituted C21 heterocycles.

Table 3 Substituted C21 pyrazoles.

Chapter 15

Table 1

In vitro

activity of 3‐substituted coumarins.

Table 2

In vitro

activity of isocoumarins and pyridopyrimidinones

Table 3 The structure–toxicology relationship (STR) of pyridopyrimidinones....

Chapter 17

Table 1 Major ISA247 metabolites observed in the various species.

Chapter 18

Table 1 Selected molecular docking programs, their algorithm characteristics...

List of Illustrations

Chapter 1

Figure 1 X‐ray crystal structure of

1

in AmpC from

Pseudomonas

.

Chapter 2

Figure 1 Mechanism of boronate transition state mimetic covalent‐reversible ...

Figure 2 Equilibrium inspires cyclic active structure design.

Figure 3 Model of

28

bound at the active site of class C β‐lac ...

Figure 4

RPX7009

bound to CTX‐M‐15. (Adapted with permission from Reference ...

Figure 5

RPX7009

bound to AmpC. (Adapted with permission from Reference 2. C...

Figure 6 Potentiation of biapenem and meropenem activity by

RPX7009

against ...

Scheme 1 Medicinal Chemistry Synthesis of Vaborbactam (

1

).

Scheme 2 Initial preparation of intermediate

29

.

Scheme 3 Kg‐scale preparation of intermediate

29

Scheme 4 The quest for solid intermediate

41

as the cGMP registered starting...

Scheme 5 Synthesis of intermediate

32

via

the new starting material

41a

.

Scheme 6 Mechanism of the Matteson chloromethylene‐insertion reaction.

Scheme 7 Initial optimized flow chemistry protocol for the Matteson reaction...

Scheme 8 Continuous loop quench. (Adapted with permission from Reference 36....

Scheme 9 Continuous stirred‐tank reactor (CSTR) cascade quench. (Adapted wit...

Chapter 3

Figure 1 Structures of anti‐flu drugs.

Figure 2 Mechanism of action of anti‐flu drugs. (Based on References 7 and 8...

Figure 3 Binding modes of baloxavir acid (

7

) and dolutegravir (

1

).

Figure 4 SAR leading to

14

.

Figure 5 SAR leading to the discovery of baloxavir marboxil (

1

).

Scheme 1 Retrosynthetic analysis of baloxavir acid (

7

).

Scheme 2 Synthesis of

22

and

23

.

Scheme 3 Synthesis of

20

.

Scheme 4 Synthesis of

21

.

Scheme 5 Synthesis of baloxavir marboxil (

1

).

Chapter 4

Scheme 1 Retrosynthesis of Ritonavir (

1

)

Figure 1

C

2

(

2

) and non‐

C

2

symmetric (

3

) core structures

Scheme 2 Synthesis of diaminodiol

2

from

N

‐Cbz

l

‐phenylalaninal

4

Scheme 3 Conversion of diol

5

to alcohol

3

Scheme 4 Synthetic methods to prepare ritonavir and its analogs

Scheme 5 The synthesis of the O‐PNP carbonate ester of 5‐(hydroxymethyl) thi...

Scheme 6 The coupling of the terminal wing pieces

17

and

19

to the protected...

Scheme 7 The preparation of [((2‐isopropylthiazol‐4‐yl) methyl) (methyl)carb...

Scheme 8 The process to the core

32a

via

(

S

)‐phenylalanine

26

Scheme 9 Salt formation/crystallization/purification of compound

3

Scheme 10 The conversion of crude

32a

–

d

to pure

N

‐Boc core hemi‐succinate

34

Scheme 11 Formation and reduction of

N

‐Boc enaminone

35

to

33a

Scheme 12 The synthesis of 5‐hydroxymethyl thiazole (

16

) from thiazolidine 2...

Scheme 13 Conversion of allyl isothiocyanate (

40

) to 5‐hydroxylmethyl thiazo...

Figure 2 Ritonavir advanced intermediates

Scheme 14 The scalable conversion of

N

‐Boc Core

34

to ritonavir (

1

)

Scheme 15 Retrosynthesis of lopinavir (

44

)

Scheme 16 Discovery lopinavir synthesis as an amorphous solid

Scheme 17 Discovery preparation of 2‐(2,6‐dimethylphenoxy)‐acetic acid (

45

)...

Scheme 18 Discovery preparation of (

S

)‐3‐methyl‐2‐(2‐oxotetrahydropyrimidin‐...

Scheme 19 Process synthesis of 2‐(2,6‐dimethylphenoxy) acetic acid (

45

)

Scheme 20 An improved synthesis of

47

Scheme 21 Alternate process synthesis of compound

47

Scheme 22 Improved coupling reactions of

63

and

67

to the core

34

Scheme 23 The shortened synthesis of lopinavir

Chapter 5

Fig . 1 Structure of ribosome, diagram by Alexandra H. Li.

Fig. 2 Left, primary binding site of tetracycline (

4

); Right, tetracycline (

Fig. 3 Relative potencies of eravacycline (

1

) vs. tetracycline (

4

) and tigec...

Chapter 6

Figure 1 Sequence comparison.

Figure 2 Crystal structure of C34. Data from PDB:3o3x.

42

(Image design by Dr...

Scheme 1 Synthesis of albuvirtide (

1

).

Figure 3 , A) The structure of the Fmoc‐protected Ramage resin., B) The struc...

Chapter 7

Figure 1 Non‐steroidal androgen receptor antagonists.

Figure 2 The relationship about darolutamide (

1

),

7

(T) and

8

(DHT).

Figure 3 Diastereomers of darolutamide

1

and metabolite keto‐darolutamide

11

Figure 4 Structure–activity relationships (SAR) of non‐steroidal AR antagoni...

Figure 5 DHT interactions in the LBD of AR (PDB: 1T7R).

22

Figure 6 Structural modification AR antagonists (

12

and

13

) of darolutamide ...

Figure 7 Darolutamide (

1

) mean area under the curve by dose in human.

26

Figure 8 Conversion between diastereomers

9

,

10

and keto‐darolutamide

11

.

Figure 9 Orion original route to darolutamide (

1

).

Figure 10 Orion chiral route to (

S,S

)‐darolutamide

9

.

Figure 11 Alternate route to darolutamide (

1

).

Figure 12 Structure of ARV‐110 (

57

).

Chapter 8

Figure 1 The crystal structures of nivatoclax (

9

),

11

, and venetoclax (

1

) bo...

Chapter 9

Figure 1 First‐, second‐, and third‐generation EGFR inhibitors.

Figure 2 EGFR induces receptor homo‐ and heterodimerization, which activates...

Figure 3 Distribution of EGFR mutations in lung cancer (Based on Reference 3...

Figure 4 The conception of lead compound optimization.

Figure 5 Two pharmacologically‐active metabolites AZ7550 and AZ5104.

Scheme 1 The retro‐synthetic route of osimertinib (

1

).

Scheme 2 AstraZeneca’s synthesis route of osimertinib (

1

)

Scheme 3 Synthetic route to osimertinib (

1

).

Scheme 4 Alternate route synthesis route of osimertinib (

1

)

Chapter 11

Figure 1 Representative first‐ and second‐generation drugs approved for the ...

Figure 2 EML4‐ALK Gene Fusion. (A) Gene orientation in a healthy cell. (B) G...

Figure 3 Crizotinib (

2

) therapy interrupts ALK dependent oncogenic signaling...

Figure 4 Potency and ADME properties of representative acyclic compounds.

a

M...

Figure 5 Left: Compound

7

cocrystal structure in the ALK kinase domain (purp...

Figure 6 SAR progression from of macrocycles to discovery of lorlatinib (

1

, ...

Figure 7 Co‐crystal structure of

9

in ALK (green) overlaid with modeled liga...

Scheme 1 Retrosynthetic analysis of lorlatinib (

1

).

Scheme 2 Synthetic route toward pyrazole

14

. (Reference 22/Google patents)

Scheme 3 Synthesis of bromopyridine

13

. (Reference 7/American Chemical Socie...

Scheme 4 Assembly of lorlatinib (

1

) using macrolactamization approach. (Refe...

Figure 8 Major by‐products formed in synthesis of lorlatinib (

1)

using the m...

Scheme 5 Assembly of lorlatinib (

1

) using intramolecular direct arylation ap...

Scheme 6 Initial scale‐up synthesis route.

Scheme 7 Manufacturing retrosynthetic strategy.

Scheme 8 Alternate scale‐up approaches to lactone

37

. (Reference 21/American...

Scheme 9 Manufacturing route to lactone

37

. (Reference 21/American Chemical ...

Scheme 10 Commercial route to lorlatinib (

1

). (Reference 24/American Chemica...

Chapter 12

Scheme 1 ADP‐ribosylation.

1

Figure 1 Timeline from PARP1 discovery to First Regulatory Approval.

5

(With ...

Figure 2 Biological mechanism of PARP1 inhibition and DNA trapping.

Figure 3 Mechanism of ADP‐ribose transfer.

19

Figure 4

In vitro

potency of niraparib (

1

) across PARP family members.

Figure 5 Structures of PARP Inhibitors.

Figure 6 Profile of Indazole

7

.

22

Figure 7 Co‐Xtal structure of niraparib

(1)

and PARP1.(Generated from PDB:...

Scheme 2 Merck Discovery Route

Scheme 3 Highlight of transaminase process route

Chapter 13

Figure 1 Normal cells maintain function by regulation of intracellular traff...

Scheme 1 Karyopharm’s synthesis of Selinexor.

Scheme 2 Watson Laboratories’ synthesis of Selinexor.

Chapter 14

Figure 3 Areas of focus to expand the SAR identified.

Figure 1 (A) Compound

29

patch clamp GABAA subtypes selectivity. (B) Medicin...

Figure 2 Zuranolone rat IV / PO plasma exposure and PK parameters from refer...

Figure 3 Human oral exposure comparison between zuranolone (

1)

, ganaxolone (

Figure 4 (A) Zuranolone (

1)

PTZ model efficacy. (B) Corresponding Zuranolone...

Chapter 16

Figure 1 Approaches to reduce blood pressure (modified from Reference

6

)

Chapter 17

Figure 1 Amino acid composition of Cyclosporin A and Voclosporin (with the l...

Figure 2 Residues at position 1 of CsA and the ISA247 stereoisomers. Structu...

Figure 3 A general protocol for isolation and purification of CsA.

Scheme 1 Synthesis of ISAtx 247.

Chapter 18

Figure 1 Concept of dynamic pharmacophore model considering of flexibility o...

Figure 2 Molecular renderings of 5HT

2B

‐transmembering (TM) helices in GPCR. ...

Figure 3 The growth of QSAR modeling is caused by the growth of experimental...

Figure 4 Overview of both supervised and unsupervised machine learning algor...

Guide

Cover Page

Title Page

Table of Contents

Copyright

Dedication

Preface

Contributing Authors

Begin Reading

Index

End User License Agreement

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Current Drug Synthesis

1st Edition

Edited by

Jie Jack LiGenHouse Bio

This edition first published 2023

© 2023 John Wiley & Sons, Inc.

All rights reserved. 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 or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Jie Jack Li to be identified as the author of the editorial material in this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication Data Applied for:

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Cover design by Wiley

Cover image: Courtesy of Brian Lanman

Dedicated to Dr. Lew Pennington

Preface

Our first four installments Wiley’s Drug Synthesis Series, Contemporary Drug Synthesis, The Art of Drug Synthesis, Modern Drug Synthesis, and Innovative Drug Synthesis were published in 2004, 2007, 2010, and 2015, respectively. They have been warmly received by the drug discovery community. The current title, Current Drug Synthesis, is our fifth installment of this series.

This book has four sections, reviewing total of 18 drugs. Section I, “Infectious Disease Drugs,” covers six drugs; Section II, “Cancer Drugs,” reviews seven drugs; Section III, “CNS Drugs,” covers two drugs; Section IV, “Miscellaneous Drugs,” covers three additional drugs.

Each chapter is divided into seven sections:

Background

Pharmacology

Structure–activity relationship

Pharmacokinetics and drug metabolism

Efficacy and safety

Syntheses

References

I am very much indebted to all contributing authors from both industry and academia. Many of them are veterans and well‐known experts in medicinal chemistry. Some of them discovered the drugs that they reviewed. As a consequence, their work tremendously elevated the quality of this book as a teaching tool.

Meanwhile, I welcome your critique and suggestions so we can make this Wiley’s Drug Synthesis Series even more useful to the drug discovery community.

Jack Li

Ann Arbor, Michigan

December 1, 2021

Contributing Authors

Dr. Nadia M. Ahmad

Charles River Laboratories

7‐9 The Spire Green Centre

Harlow, CM19 5TR

United Kingdom

Dr. Narendra Ambhaikar

Neuland Laboratories Limited

R&D Centre, Bonthapally Village

Gummadidala Mandal

Sangareddy District (near Hyderabad)

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Dr. Yvonne M. Angell

GenEdit, Inc.

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South San Francisco, CA 94080

United States

Ruby M. Aaron

Department of Chemistry and

Biochemistry

Colorado College

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ChemPartner

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Qpex Biopharma, Inc.

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HEC R&D Center

Pharmaceutical Science

Dongguan GuangDong

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ChemPartner

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ChemPartner

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Guangzhou City Key Laboratory of

Precision Chemical Drug Development,

School of Pharmacy

Jinan University

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Guangzhou 510632, P. R. China

Prof. Amy B. Dounay

Department of Chemistry and

Biochemistry

Colorado College

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Colorado Springs, CO 80903

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Dr. Wendy J. Hartsock

CEM Corporation

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Matthews, NC 28104

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Qpex Biopharma, Inc.

6275 Nancy Ridge Dr., Suite 100

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Dr. Brian A. Lanman

Amgen, Inc.

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Hayden K. Low

Department of Chemistry and

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Colorado College

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ChemPartner

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NuChem Sciences

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Medicinal Chemistry

Olema Oncology

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Dr. Andrew T. Parsons

Amgen, Inc.

1 Amgen Center Drive

Thousand Oaks, CA 91320

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Qpex Biopharma, Inc.

6275 Nancy Ridge Dr., Suite 100

San Diego, CA 92121

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Timothy M. Reichart

Department of Chemistry

Hampden‐Sydney College

Hampden‐Sydney, VA 23943

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Benjamin T. Sokol

Department of Chemistry and

Biochemistry

Colorado College

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Dr. Yan Wang

ChemPartner

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Small Molecule Drug Discovery

Bristol Myers Squibb Research and

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Dr. Dexi Yang

Merck Research Lab

Merck & Company, Inc.

Kenilworth, NJ 07033

United States

Dr. Ji Zhang

HEC R&D Center

Pharmaceutical Science

Dongguan GuangDong

P. R. China

Fengtao Zhou

Guangzhou City Key Laboratory of

Precision Chemical Drug Development

School of Pharmacy

Jinan University

601 West Huangpu Avenue

Guangzhou 510632, P. R. China

IINFECTIOUS DISEASE DRUGS

1Relebactam (Recarbrio), A β‐Lactamase Inhibitor for the Treatment of cIAI/cUTI/HABP/VABP

Dexi Yang

1. Background

The discovery of antibiotics is revolutionary in chemotherapy against infectious diseases in modern medicine history. Unfortunately, after its golden era from the 1950s to 1970s, antimicrobial resistance among common bacterial pathogens became a new threat to public health. Recently, WHO enlisted antibiotic resistance in the top three public health threats. Infections caused by multidrug‐resistant organism became a new economic burden in health‐care system. In the United States alone, it costs over 20 billion dollars per year, and more than 23,000 people died of infection with antibiotic‐resistant annually. With this continuing, CDC estimated that victims will culminate to more than 300 million globally with loss of over 100 trillion dollars by 2050. The stake is high enough to draw more attention to invent new therapeutics to treat infected patients.1

Of all known antimicrobial resistance, carbapenem resistance in gram‐negative pathogens is the most critical. Clinically, carbapenems are considered the most active and potent agents against MDR gram‐negative pathogens. They are the last silver bullets to kill superbugs. However, according to the global priority list of antibiotic‐resistant bacteria published by WHO in 2017, three of the top four pathogens critical for developing antibiotics are carbapenem‐resistant, and they are Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii.2,3 In the 1990s, research on MDR revealed that antibiotic resistance of gram‐negative bacteria is mainly caused by three mechanisms. The major mechanism of resistance to carbapenems is the production of β‐lactamase. It has been identified that MDR gram‐negative pathogens produces at least four classes of β‐lactamases: A, B, C, and D.4 They all can degrade antibacterial agents and make them ineffective. In addition to these enzymes, these pathogens also developed other mechanisms to make antibiotics less efficient. One is porin mutation caused by porin expression. This renders the outer bacterial membrane impermeable to antibacterial. The other is efflux pump upregulation. Via efflux pump, antibiotics are pumped out of the membrane of bacteria and lose their therapeutic efficacy.3,4 Based on all these three mechanisms, new generations of β‐lactamase inhibitors should not only have high potency to help carbapenem restore potency, but also possess appropriate physicochemical properties to increase permeability and decrease efflux rate.

Guided by this strategy, in the past decade, several combinations of antibiotic with β‐lactamase inhibitors, such as polymyxins, ceftazidime‐avibactam, ceftolozane– tazobactam, metropenem–veborbactam, etc., have been discovered and approved by FDA.5–7 But most of them are only effective against a small portion of pathogens, and with no surprise, gradually loose efficacy due to evolved resistance. As a result, new therapeutic options against gram‐negative organisms with resistance are still urgently needed.

Recarbrio was approved in July 2019 as an alternative treatment option of adults with complicated urinary tract infections (cUTI), including pyelonephritis, and complicated intra‐abdominal infections (cIAI) caused by susceptible gram‐negative bacteria.8,9 Recarbrio is a three‐drug combination injection containing imipenem, cilastatin, and relebactam (1). Imipenem is a carbapenem that inhibits cross‐linking of peptidoglycan during cell wall synthesis by deactivating penicillin binding proteins. It is co‐administered with cilastatin, a dehydro‐peptidase‐I inhibitor to reduce renal metabolism of imipenem. Cilastatin itself does not have antibacterial activity. Relebactam (1) is a novel β‐lactamase inhibitor. It alone has no antibacterial activity either. Its function is to protect imipenem by inhibiting Ambler class A (e.g., KPCs), class C (e.g., AmpC) β‐lactamases, and PDC. In vitro, the addition of relebactam (1) significantly improves the antibacterial activity of imipenem by lowering the minimum inhibitory concentration of imipenem by 2‐ to 128‐folds against ESBL or KPC producing enterobacterales, as well as MDR or imipenem‐resistant isolates.10

In June 2020, FDA further approved a supplemental new drug application (sNDA) for Recarbrio for the treatment of patients 18 years of age and older with hospital‐acquired bacterial pneumonia and ventilator‐associated bacterial pneumonia (HABP/VABP), caused by a group of susceptible gram‐negative microorganism.9

It worth mentioning that relebactam (1) is inactive against class B metallo‐β‐lactamases (e.g., NDM, VIM, and IMP) and class D oxacillinases (e.g., OXA‐48). This leaves space for further development of novel BLIs with expanded coverage of class B metallo‐β‐lactamase and class D β‐lactamase to secure efficacy of new antibiotics.

2. Pharmacology

Imipenem (trade name Primaxin) is an intravenous β‐lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid‐1970s.10 As a carbapenem, it is highly resistant to the β‐lactamases produced by MDR gram‐negative bacteria. It inhibits cross‐linking of peptidoglycan during cell wall synthesis by deactivating penicillin binding proteins, thereby causing bacterial cell lysis and death.11 Since it rapidly degraded by the renal enzyme dehydropeptidase‐I when administered alone, imipenem is always co‐administered with cilastatin, a dehydropeptidase‐I inhibitor to reduce renal metabolism. Ever since its approval, it played a key role in treating infections caused by susceptible strains when other antibiotics failed. However, since more and more bacteria developed drug‐resistance via production of β‐lactamase, imipenem became less effective in some patients. It is necessary to invent new β‐lactamase inhibitors as additive to restore the antibacterial activity of imipenem.

Relebactam (MK‐7655) is a novel β‐lactamase inhibitor discovered by Merck scientists as part of a drug discovery program aimed at novel BLI in 2008. Over several lead series, a bridged class showed broad spectrum of activities. Its cyclic urea can open and bind covalently to an active site serine within Ambler class A, C, and D β‐lactamases. To be specific, the constrained five‐membered urea bridge facilitates acylation reaction between the C‐7 carbonyl and a serine residue within the β‐lactamase active site. Modeling studies suggested that the N,O‐oxysulfate group can further stabilize the ring‐opened acyl‐β‐lactamase intermediate via hydrogen‐bond formation with neighboring catalytic site residues. As a result, the covalent bond blocks the active site of the β‐lactamase, stops hydrolysis of imipenem, and restores its bactericidal activity.12

So far, it is active in inhibiting Ambler class A (e.g., KPCs) and class C (e.g., AmpC) actamases and PDC, but inactive against class B metallo‐β‐lactamases (e.g., NDM, VIM and IMP) and class D oxacillinases (e.g., OXA‐48).13In vitro, the addition of relebactam (1) significantly improves the antibacterial activity of imipenem by lowering the minimum inhibitory concentration of imipenem by 2‐ to 128‐folds against ESBL or KPC producing enterobacterales, or imipenem‐resistant isolates. Neither imipenem nor relebactam is subject to efflux, which is an advantage against strains that overexpress efflux pumps.

3. Structure–Activity Relationship (SAR)

The lead compound for the relebactam (1) project has two sources: one is MK‐8712, a monobactam β‐lactamase inhibitor only effective against class C β‐lactamase; the other is avibactam sodium (NXL‐104), a covalent and reversible non‐β‐lactam β‐lactamase inhibitor to β‐lactamase TEM‐1 and CTX‐M‐15.14 In order to expand the coverage of novel BLI to both class C (PDC) P. aeruginosa and class A (KPC) enterobacterales class A and class C β‐lactamases, Merck scientists took a hybrid approach by incorporating novel heterocyclic amide side chains for MK‐8712 with the bridged core of NXL‐104. After overcoming many synthetic difficulties, a series of bridged bicyclic urea with basic heterocyclic side chains have been prepared for SAR study.

As shown in Table 1, selected compounds were evaluated in enzyme inhibition assays and in vitro synergy assays.12 The enzyme inhibition assays measured each compound’s ability to inhibit the hydrolysis of nitrocefin by four β‐lactamase: one class A BL, two class C BLs and one class D BL. The synergy data reported the concentration of each compound to reduce the MIC of imipenem to 4 μg/mL against the strains of Pseudomonas, Klebsiella, and Acinetobacter.

Let us discuss the result from the piperidine analog 1, which was later developed as Merck’s clinical compound relebactam (1). From enzyme inhibition assay we can see it inhibits KPC‐2, which is the key class A BL responsible for carbapenem resistance in Klebsiella pneumoniae, as well as AmpC, the BL responsible for the resistance in Pseudomonas. However, it shows weak inhibition against AmpC, and no effect against the class D enzyme Oxa‐40. Fortunately, the latter two enzymes account for very little portion of clinical cases. It is delighting to see analog 1 also effectively synergized imipenem against Klebsiella and Pseudomonas, with concentrations of 12.5 and 4.7 μM, to reduce the imipenem MIC to 4 μg/mL. Just like the piperidine analog 1, the seven membered azepine analog 6 and five membered pyrrolidine analog 7 all showed similar activities in the enzyme and synergy assays. Alkylation of the piperidine nitrogen as in analog 8 has nearly no effect on enzyme activity and synergy. From the X‐ray crystal structure (Figure 1) of 1 bound in the active site of AmpC (Pseudomonas), it can be easily seen that hydrogen bonding between piperidine free N and backbone of AmpC is a key interaction. Other than that, the amide and the N,O‐oxysulfate are also important for potency and should be considered for future target design.

Figure 1 X‐ray crystal structure of 1 in AmpC from Pseudomonas.

Table 1 SAR of bridged bicyclic urea β‐lactamase inhibitors

aBLI (μM) to reduce IPM MIC to 4 μg/mL.

Replacement of saturated heterocycles with aromatic heterocycles was also considered. Results shown obvious enhancement in β‐lactamase enzyme inhibition (as in analog 9), but a substantial loss in synergy activity with imipenem is disappointing. It is mainly due to increased efflux from bacterial cells as the nitrogen in aromatic heterocycles would not be protonated at physiological pH. For comparison, a positive charge was introduced by preparing a hard‐quaternary analog 10. It is not surprised that the compound is substantially less reactive than corresponding aromatic analog 9 in enzyme inhibition. It can be concluded that saturated heterocycles are the best with considering both enzyme inhibition and in vitro synergy.

As for the amide linker, methylation on the nitrogen was prepared, and it caused substantial loss in enzyme inhibition as shown in analog 11. Replacement of the amide linker with an ester was also considered, although analog 12 showed comparable enzyme inhibition and similar activity in the synergy assay, further stability study and efflux studies proved it inferior to analog 1.

In general, most heterocyclic side chains were tolerated and the resulting compounds had activity against both class A and class C β‐lactamases. No inhibition against class D was observed. After balancing all pros and cons, not only these assay data, but also efflux and comprehensive ADMET properties, analog 1 is superior to others and selected for further development.

4. Pharmacokinetics and Drug Metabolism

The pharmacokinetic properties of imipenem/cilastatin are not affected by relebactam. Cmax and AUC of imipenem, cilastatin, and relebactam (1) are all increased proportionally with dose. After administered by intravenous infusion over 30 min every 6 hour at a dose of 1,250 mg (imipenem/cilastatin 500/500 mg plus relebactam (1) 250 mg) every 6 hour, steady‐state Cmax of imipenem and relebactam reached 88.9 μM and 58.5 μM, respectively, with AUC from 0 to 24 hour 500 μM·h for imipenem and 390.5 μM·h for relebactam (1). Their PPBs are 20% for imipenem, 40% for cialastin, and 20% for relebactam (1). Their Vds at steady state are 24.3 L for imipenem, 13.8 L for cialastin, and 19.0 L for relebactam.

In Recarbrio, imipenem is exclusively metabolized in the kidney by dehydropeptidase‐I. To decrease renal metabolism, cilastatin, a dehydropeptidase‐I inhibitor, is co‐administered. Although relebactam (1) is minimally metabolized by renal, it is mainly excreted renally. After multiple dose administrations in healthy individuals, 63% of imipenem, 77% of cilastatin, and > 90% of relebactam doses were recovered in human urine. Half‐lives of imipenem/cilastatin and relebactam (1) are 1.0, 1.2 hour respectively. Since no ingredient is an inhibitor or inducer of the cytochrome P450 enzyme system, Recarbrio has no obvious drug–drug interactions.15

Sex, race, age, and weight have no impact on PK. Since it mainly excreted renally, hepatic impairment has no effect, while renal impairments have substantial influence. Exposure in patients with mild, moderate, or severe renal impairment was 1.22–2.01 times for imipenem, and 1.38–3.05 times for relebactam (1). Dose adjustment therefore is required.8,9

5. Efficacy and Safety

In Table 1, we have already seen imipenem/relebactam showed broad‐spectrum in vitro inhibitory activity on both class A (K. pneumoniae) and class C (P. aeruginosa) β‐lactamase enzymes. Actually, of over 6,000 P. aeruginosa isolates collected in 2016 in a surveillance study, 90% were fully susceptible at the approved FDA imipenem/REL breakpoint of 2 mg/L, while only 67% of the isolates were susceptible to imipenem without REL. Additionally, the percent imipenem and imipenem/REL susceptibility for 145 molecularly‐sequenced KPC isolates was 9.9% and 98.0%, respectively, demonstrating the effectiveness of REL in restoring antibacterial activity of imipenem in KPC‐producing clinical isolates.16a

The in vivo efficacy of Recarbrio was demonstrated in mouse spleen (P. aeruginosa and K. pneumoniae) and lung (P. aeruginosa) models of infection and afforded greater than a 3‐log reduction in colony forming units (CFU) following intravenous (IV) administration. Based on these clinical studies, the pivotal phase III trial RESTORE‐IMI 1 was conducted. Recarbrio was administered via intravenous infusion in two trials, one each for cUTI and cIAI. The cUTI trial included 298 adult patients with 99 treated with Recarbrio. The cIAI trail included 347 patients with 117 treated with Recarbrio. And later, more assessments were conducted in the phase III trials of adults (age ≥ 18 years) with Hospital‐Acquired or Ventilator‐Associated Bacterial Pneumonia (HABP/VABP). All treatments achieved favorable overall response. In all these clinical trials, imipenem/cilastatin/relebactam showed good tolerance in patients with cUTI, cIAI, or HABP/VABP, and their safety profiles were the same as those established for imipenem/cilastatin alone.16

Observed adverse effects are mainly from imipenem‐cilastation (Primaxin). Since generalized seizures have been reported when ganciclovir was co‐administered with imipenem/cilastatin, Recarbrio should be avoided being taken with the anticonvulsant valproic acid, divalprox sodium, or the antiviral ganciclovir, unless the potential benefits outweigh the risks. It may reduce the level of corresponding API and increase the risk of seizure in the patients taking these drugs to control seizure. In addition, there were also reported CNS adverse reactions with patients with preexisting CNS disorders and/or those with compromised renal function. For these patients, neurological evaluation should be conducted to determine before taking Recarbrio.17

6. Syntheses

6.1. Early Process Synthesis

The compound has two features made its synthesis difficult: one is the bicyclo[3.2.1]urea bridge, and the other is its existence as a zwitterionic salt. Due to low solubility and high reactivity of the final product, the urea bridge had to be constructed as late as possible, so did the formation of Zwitterionic salt. The evolution in its synthesis can be clearly tracked from the several generations of synthesis routes published.18 Here we will focus on two synthetic routes from process chemists. The earlies route from medicinal chemists took up to 17 steps can be found in the patents.18a,b

In one earlier process chemistry route, the piperidine ring was prepared by ring expansion of the known chiral (S)‐N‐Bocpyroglutamic acid 13.18e The lactam was first opened by sulfur ylide generated in situ from trimethylsulfoxonium iodide and potassium tert‐butoxide. The ring opening intermediate 14 was carried forward without further workup. Sequential treatment of 14 with benzyloxyammonium chloride and LiCl in DMSO rendered α‐chlorooxime 15. DMSO is critical to this reaction as it can suppress undesired displacement of the chloride by residual iodide in the reaction mixture carried from trimethylsulfoxonium iodide. With no surprise, ring closure was swiftly achieved by treating the α‐chlorooxime 15 with potassium tert‐butoxide in DMF at 0 °C, and the resulting intermediate 16 was deprotected by TMSBr and N,O‐bis(trimethylsilyl)‐acetamide to give piperidine 17.

The oxime in 17 existed as a mixture of (E)‐ and (Z)‐isomers. After screening reduction conditions for C=N bond, sodium borohydride/triglyme was selected to deliver the desired product 18 with high diastereoselectivity, mainly directed by the carboxylic acid. Conversion of the hydroxylamine to sulfuric acid salt enabled isolation of crystalline form with 99.2:0.8 dr. Due to low solubility of sulfuric acid salt, it was converted to trifluoroacetate first, followed by amidation with amino piperidine to give amide 19. The TFA salt was further converted to tosylate salt for easy crystallization, and compound 20 with high purity (> 99.5%) was separated as a salt.

Construction of the reactive bicyclo[3.2.1]urea bridge from diamine 20 proved to be very challenging. Most carbonyl sources are added preferentially at the piperidine nitrogen, without further cyclization to make the bridged urea. After trials and errors, the cyclization finally succeeded with triphosgene in the presence of excess Hünig’s base, followed by dilute aqueous phosphoric acid. Urea 21 was crystalized with 87% isolated yield. Deprotection of benzyl group in THF gave free N‐hydroxylamine, which was sulfated with SO3•pyridine to give desired product 22. Finally, TMSI in acetonitrile was able to deprotect Boc and give the desired final product 1.

6.2 Later Process Synthesis

After further optimization, Merck process chemists reported several new routes, and the following one is the most efficient and economical for scalable multikilogram synthesis.18f

This route started from optically pure cis‐5‐hydroxypipecolic acid 23 available from enzymatic oxidation of pipecolic acid, avoiding more expensive earlier approach. Upon treatment with 2 equiv of 2‐NsCl, one for N‐protection, the other to active the carboxylic acid to facilitate cyclization to give lactone 24 in > 99% purity. The lactone was then opened readily with commercially Boc‐protected aminopiperidine in THF, and the resulting intermediate was treated with another 2 equiv of 2‐NsCl in one pot to give desired sulfonate ester 25 in 98% yield for 2 steps from 24. Subsequent displacement of 2‐NsO with protected –OBn hydroxylamine, followed by removal of all 2‐Ns gave neutral form of compound 20 in 70% yield with > 97.5% HPLC purity. From 20, the same chemistry as mentioned before was able to furnish the synthesis of 1. This new route provided a more efficient way for the synthesis in only eight steps and 42% overall yield.

7. Summary

In summary, Recarbrio is a fixed dose combination of imipenem, cilastatin, and relebactam (1). It was approved by FDA in July 2019 for the treatment of adults with limited treatment options for cUTI and cIAI caused by a range of susceptible gram‐negative bacteria, including but not limited to Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, K. pneumoniae, and P. aeruginosa. In June 2020, it was further approved to treat hospital‐acquired bacterial pneumonia and ventilator‐associated bacterial pneumonia (HABP/VABP) in patients 18 years of age and older. Recarbrio is administered by intravenous infusion over 30 minutes every 6 hours at a recommended dose of 1.25 g (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg), with dose adjustments for patients with renal impairment. In addition to its pharmacology, PK, metabolism, safety, and SAR, two of its process syntheses have also been discussed in this chapter. As the last treatment options for carbapenem‐resistant gram‐negative infections, antimicrobial stewardship should be set up to ensure appropriate use of this new therapeutic agent.

8. References

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