Lead Optimization for Medicinal Chemists E-Book

Florencio Zaragoza Dörwald

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch
• Veröffentlichungsjahr: 2013

Seitenzahl: 217

Beschreibung

Small structural modifications can significantly affect the pharmacokinetic properties of drug candidates. This book, written by a medicinal chemist for medicinal chemists, is a comprehensive guide to the pharmacokinetic impact of functional groups, the pharmacokinetic optimization of drug leads, and an exhaustive collection of pharmacokinetic data, arranged according to the structure of the drug, not its target or indication. The historical origins of most drug classes and general aspects of modern drug discovery and development are also discussed. The index contains all the drug names and synonyms to facilitate the location of any drug or functional group in the book. This compact working guide provides a wealth of information on the ways small structural modifications affect the pharmacokinetic properties of organic compounds, and offers plentiful, fact-based inspiration for the development of new drugs. This book is mainly aimed at medicinal chemists, but may also be of interest to graduate students in chemical or pharmaceutical sciences, preparing themselves for a job in the pharmaceutical industry, and to healthcare professionals in need of pharmacokinetic data.

Leseprobe

Table of Contents

Related Titles

Title Page

Copyright

Introduction

Glossary and Abbreviations

Part I: Introduction

Chapter 1: The Drug Discovery Process

1.1 Pharmacokinetics–Structure Relationship

1.2 The Future of Small-Molecule Drugs

References

Chapter 2: Lead Optimization

2.1 What Limits/Reduces Oral Bioavailability?

2.2 What Limits/Reduces Plasma Half-Life?

2.3 How to Improve bbb-Penetration?

2.4 How to Avoid CYP Inhibition/Induction?

2.5 How to Avoid Interaction with the Human Ether-à-go-go-Related Gene (hERG)?

2.6 How to Prevent Toxicity?

2.7 Examples of PK-Optimization in Animals

References

Part II: The Pharmacokinetic Properties of Compound Classes

Chapter 3: Alkanes

3.1 Metabolism

References

Chapter 4: Alkenes and Alkynes

4.1 Metabolism

References

Chapter 5: Arenes

5.1 Metabolism

Chapter 6: Halides

6.1 Fluorine

6.2 Chlorine

6.3 Bromine

6.4 Iodine

6.5 Alkylating Agents

Reference

Chapter 7: Azides

Chapter 8: Nitro Compounds

8.1 Metabolism

Chapter 9: Azo Compounds

Chapter 10: Triazenes

Chapter 11: Nitrates and Nitrites

Further Reading

Chapter 12: N-Nitroso Compounds

Chapter 13: N-Oxides

Chapter 14: Alcohols

14.1 Metabolism

Chapter 15: Phenols

References

Chapter 16: Ethers

16.1 Metabolism

Reference

Chapter 17: Epoxides

Chapter 18: Peroxides

Chapter 19: Thiols

Chapter 20: Thioethers

20.1 Metabolism

Reference

Chapter 21: Sulfoxides

Chapter 22: Sulfones

Chapter 23: Aliphatic Amines

23.1 Basicity

23.2 Metabolism

23.3 Rates of N-Dealkylation

Reference

Chapter 24: Quaternary Ammonium Salts

Reference

Chapter 25: Amidines

Reference

Chapter 26: Guanidines, Acylguanidines, and Biguanides

26.1 Acylguanidines

26.2 Biguanides

Reference

Chapter 27: Anilines

27.1 Metabolism

Chapter 28: Hydrazines, Acylhydrazines, and Hydrazones

Chapter 29: Aldehydes

Chapter 30: Ketones

Chapter 31: Carboxylic Acids

31.1 Metabolism

31.2 Bioisosteres of Carboxylic Acids

31.3 Amino Carboxylic Acids, N-Acyl Amino Acids,and Related Compounds

References

Chapter 32: Carboxylic Esters

Reference

Chapter 33: Amides

Chapter 34: Lactams and Imides

34.1 Pyrazolone Antipyretics

34.2 Five-Membered Lactams as Nootropics

References

Chapter 35: Nitriles

References

Chapter 36: Carbonates

Chapter 37: Carbamates

37.1 Carbamates as Hypnotics

References

Chapter 38: Ureas

Reference

Chapter 39: Thiocarbonyl Compounds

Chapter 40: Sulfonic Acids

Chapter 41: Sulfonic Esters

Chapter 42: Sulfates and Sulfamic Acids

Chapter 43: Phosphonic Acids

Chapter 44: Phosphoric Acid Derivatives

Chapter 45: N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds

Reference

Chapter 46: Arylalkylamines

46.1 Antihistaminics: History

Reference

Chapter 47: Phenethylamines (2-Phenylethylamines)

47.1 Biological Activity of Phenethylamines

47.2 Metabolism

47.3 Tetrahydroisochinolines and Related Compounds

Further Reading

Chapter 48: Aminoalkylindoles and Indole Alkaloids

Reference

Chapter 49: Phenothiazines

49.1 Metabolism

References

Chapter 50: Dibenzazepines and Related Tricyclic Compounds

Chapter 51: 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; “β-Blockers”)

51.1 Metabolism

Chapter 52: Opiates

Reference

Chapter 53: N-(Carboxyalkyl)-α-Amino Acid Amides (Prils)

Reference

Chapter 54: Anilides and Amides of Glycine

Chapter 55: Peptides, Peptidomimetics, and Related Oligoamides

55.1 Peptidomimetics

55.2 Thrombin Inhibitors and Related Compounds

References

Chapter 56: Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas

References

Chapter 57: Imidazoles

References

Chapter 58: Triazoles

Chapter 59: Pyridines, Pyrimidines, and Related Compounds

59.1 Proton Pump Inhibitors

References

Chapter 60: Quinolines

60.1 Tecans

60.2 Quinazolines

References

Chapter 61: Nucleoside Analogs

Reference

Chapter 62: Dihydropyridines

Chapter 63: Arenesulfonamides

63.1 Antibacterials

63.2 Diuretics

Reference

Chapter 64: Sulfonylureas

Chapter 65: Benzodiazepines

Reference

Chapter 66: Steroids

References

Chapter 67: Anthracyclines

Chapter 68: Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDS)

68.1 Salicylates

References

Chapter 69: Quinolonecarboxylic Acids (Gyrase Inhibitors)

Chapter 70: β-Lactams

70.1 Cephalosporins

Reference

Chapter 71: Prostaglandin Analogs

Chapter 72: Sartans

Reference

Chapter 73: Statins

Chapter 74: Folic Acid Analogs (Antifolates)

Chapter 75: Taxanes

Reference

Chapter 76: Macrocyclic Compounds

Reference

Index

Related Titles

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The Author

Dr. Florencio Zaragoza Dörwald

Lonza AG

Rottenstrasse 6

3930 Visp

Switzerland

Cover illustration: Mobile in the style of Alexander Calder.

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Introduction

The aim of this book is to provide medicinal chemists with a guide to the effect of structural modifications and functional groups on the pharmacokineticPharmacokinetic (PK) properties of compounds, illustrated by a full collection of PK data. How does the plasma half-life and oral bioavailability change on small structural modifications? Which structural elements are allowed for a drug, and which are interchangeable, without significantly altering the PK properties? How can the oral bioavailability and half-life of a lead be increased? Questions of this type, critical to every small molecule drug development program, are addressed herein.

The tables contain most drugs for which human PK data have been reported. Some compounds in clinical development or with animal PK data only have also been included. The compounds listed include currently available drugs, withdrawn drugs, and compounds that failed during clinical trials. Compounds are arranged by keeping structurally closely related drugs together, to show variations of PK properties on minimal structural modification. This kind of information should be particularly valuable for medicinal chemists in their endeavor to improve the PK of their leads.

PK data are no natural constants inherent to a compound, such as its melting point or density, but depend on the sex, age, and condition of the patient, his diet, the dose of the drug, and the hour at which the measurement is performed. In a typical study with 5–10 healthy volunteers, half-life and oral bioavailability may show strong interindividual variations. Even for a single patient, PK properties of a drug will change with each new dosing. Thus, the establishment of a true PK SAR (structure activity relationshipStructure Activity Relationship) for drugs would require PK data obtained from huge groups of people. Understandably, such information is not available.

The accuracy of compound quantization in plasma and thus the quality of PK data has increased dramatically in recent years. Moreover, a more complete PK profile is requested today by the regulatory agencies than in the past. Therefore, older PK data is usually less accurate and less complete than more recent data.

Because PK is highly variable between individuals, even high-quality data must be used with caution by physicians. Also, medicinal chemists should keep in mind that (i) reported PK values are always inaccurate and (ii) vary strongly between patients. Nevertheless, short of anything better, the values reported herein should give chemists an estimate of the PK properties of compound classes and a knowledge of how structural modifications will probably affect PK.

The PK data and other information presented herein was collected from various sources:

1. Books: Goodman and Gillman's The Pharmacological Basis of Therapeutics, 9th edn, Hardman, J. G.; Limbird, L. E. eds., McGraw-Hill, 1996. Forth, W.; Henschler, D.; Rummel, W. Pharmakologie und Toxikologie. Mannheim: B.I. Wissenschaftsverlag, 1987. Jack, D. B. Handbook of Clinical Pharmacokinetic Data. Macmillan Publishers Ltd, 1992. Bochner, F.; Carruthers, G.; Kampmann, J.; Steiner, J. Handbook of Clinical Pharmacology, 2nd edn, Boston, Toronto: Little, Brown & Co, 1983;

2. Peer-reviewed publications, for example, Obach, R. S.; Lombardo, F.; Waters, N. J. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab. Dispos., 2008, 36, 1385–1405; Smith, D. A.; Jones, B. C.; Walker, D. K. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Medicinal Research Reviews, 1996, 16, 243–266;

3. Public online databases: EMA-filings (www.ema.europa.eu), the swiss Arzneimittel Kompendium (www.kompendium.ch), the drug bank (www.drugbank.ca), banque des données automatisée sur les medicaménts (www.biam2.org), clinical drug use (www.clinicaldruguse.com), PharmGKB (www.pharmgkb.org), medsafe (www.medsafe.govt.nz).

On minor discrepancies between sources, the mean value was calculated. In case of major inconsistencies, preference was given to newer data. ClearanceClearance (CL) is reported as given in the literature; its consistency with the reported values of t1/2 and V was not verified.

The values for polar surface areaPolar Surface Area (PSA) and log P were calculated with ACD/Labs (Advanced Chemistry DevelopmentAdvanced Chemistry Development), Version 11.02 (uncharged compounds), or with Molinspiration Cheminformatics (www.molinspiration.com) (charged compounds).

The historical background of many drugs and therapeutic strategies was gathered from the books cited above, from peer-reviewed articles, and from the excellent assays of Walter Sneader, Professor at the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow, Scotland.

Glossary and Abbreviations

Part I

Introduction

Chapter 1

The Drug Discovery Process