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 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