Lead Optimization for Medicinal Chemists

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

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.