Lead Optimization for Medicinal Chemists (eBook)

Florencio Zaragoza Dörwald studied chemistry at the Georg-August University in Göttingen, Germany, and Université LouisPasteur, Strasbourg, France, where he obtained his Ph.D. in 1990 on the synthesis of natural products under the guidance of M. Franck-Neumann and M. Miesch. He spent one postdoctoral year in both the groups of A. Pfaltz (University of Basel) and A. P. Marchand (University of North Texas), and then worked on the synthesis of unnatural amino acids at the Technical University of Dresden. From 1994 to 2007 he had a position as a medicinal chemist at Novo Nordisk A/S, Denmark. Currently, he is employed as organic chemist at Lonza AG in Visp, Switzerland.

PART I: Introduction

THE DRUG DISCOVERY PROCESS
Pharmacokinetics - Structure Relationship
The Future of Small-Molecule Drugs

LEAD OPTIMIZATION
What Limits/Reduces Oral Bioavailability?
What Limits/Reduces Plasma Half-Life?
How to Improve bbb-Penetration?
How to Avoid CYP Inhibition/Induction?
How to Avoid Interaction with the HumanEther-'a-go-go-Related Gene (hERG)?
How to Prevent Toxicity?
Examples of PK-Optimization in Animals

PART II: The Pharmacokinetic Properties of Compound Classes

ALKANES
Metabolism

ALKENES AND ALKYNES
Metabolism

ARENES
Metabolism

HALIDES
Fluorine
Chlorine
Bromine
Iodine
Alkylating Agents

AZIDES

NITRO COMPOUNDS
Metabolism

AZO COMPOUNDS

TRIAZENES

NITRATES AND NITRITES

N-NITROSO COMPOUNDS

N-OXIDES

ALCOHOLS
Metabolism

PHENOLS

ETHERS
Metabolism

EPOXIDES

PEROXIDES

THIOLS

THIOETHERS
Metabolism

SULFOXIDES

SULFONES

ALIPHATIC AMINES
Basicity
Metabolism
Rates of N-Dealkylation

QUATERNARY AMMONIUM SALTS

AMIDINES

GUANIDINES, ACYLGUANIDINES, AND BIGUANIDES

Acylguanidines
Biguanides

ANILINES
Metabolism

HYDRAZINES, ACYLHYDRAZINES, AND HYDRAZONES

ALDEHYDES

KETONES

CARBOXYLIC ACIDS
Metabolism
Bioisosteres of Carboxylic Acids
Amino Carboxylic Acids, N-Acyl Amino Acids, and Related Compounds


CARBOXYLIC ESTERS

AMIDES

LACTAMS AND IMIDES
Pyrazolone Antipyretics
Five-Membered Lactams as Nootropics

NITRILES

CARBONATES

CARBAMATES
Carbamates as Hypnotics

UREAS

THIOCARBONYL COMPOUNDS
SULFONIC ACIDS

SULFONIC ESTERS

SULFATES AND SULFAMIC ACIDS

PHOSPHONIC ACIDS

PHOSPHORIC ACID DERIVATIVES

N-(AMINOALKYL)BENZAMIDES, -BENZOATES, AND RELATED COMPOUNDS

ARYLALKYLAMINES
Antihistaminics: History

PHENETHYLAMINES (2-PHENYLETHYLAMINES)
Biological Activity of Phenethylamines
Metabolism
Tetrahydroisochinolines and Related Compounds

AMINOALKYLINDOLES AND INDOLE ALKALOIDS

PHENOTHIAZINES
Metabolism

DIBENZAZEPINES AND RELATED TRICYCLIC COMPOUNDS

3-ARYLOXY-2-HYDROXYPROPYLAMINES (B-ADRENERGIC ANTAGONISTS; 'B-BLOCKERS')
Metabolism

OPIATES

N-(CARBOXYALKYL)-a-AMINO ACID AMIDES (PRILS)

ANILIDES AND AMIDES OF GLYCINE

PEPTIDES, PEPTIDOMIMETICS, AND RELATED OLIGOAMIDES
Peptidomimetics
Thrombin Inhibitors and Related Compounds

OLIGOARYLAMINES, OLIGOARYLAMIDES, OLIGOARYLCARBAMATES, AND OLIGOARYLUREAS

IMIDAZOLES

TRIAZOLES

PYRIDINES, PYRIMIDINES, AND RELATED COMPOUNDS
Proton Pump Inhibitors

QUINOLINES
Tecans
Quinazolines

NUCLEOSIDE ANALOGS

DIHYDROPYRIDINES

ARENESULFONAMIDES
Antibacterials
Diuretics

SULFONYLUREAS

BENZODIAZEPINES

STEROIDS

ANTHRACYCLINES

ARYLACETIC, BENZOIC, AND RELATED CARBOXYLIC ACIDS (NSAIDS)
Salicylates

QUINOLONECARBOXYLIC ACIDS (GYRASE INHIBITORS)

B-LACTAMS
Cephalosporins

PROSTAGLANDIN ANALOGS

SARTANS

STATINS

FOLIC ACID ANALOGS (ANTIFOLATES)

TAXANES

MACROCYCLIC COMPOUNDS