Lead Optimization for Medicinal Chemists -- Contents -- Introduction -- Glossary and Abbreviations -- Part I Introduction -- 1 The Drug Discovery Process -- 1.1 Pharmacokinetics-Structure Relationship -- 1.2 The Future of Small-Molecule Drugs -- References -- 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 -- 2.7.1 Dihydroorotate Dehydrogenase Inhibitors -- 2.7.2 Matrix Metalloproteinase Inhibitors -- 2.7.3 Antibacterial Aminobenzenesulfonamides -- 2.7.4 Tyrosine Kinase Inhibitors -- 2.7.5 5-HT1A Agonists -- 2.7.6 Dipeptidyl Peptidase IV Inhibitors -- Structural Variations of Sitagliptin -- 2.7.7 P-Selectin Inhibitors -- 2.7.8 β3-Adrenergic Agonists -- 2.7.9 Vanilloid-1 Antagonists -- 2.7.10 HIV Protease Inhibitors -- 2.7.11 Matrix Metalloproteinase Inhibitors (Tested in Rats) -- 2.7.12 HIV Integrase Inhibitors -- 2.7.13 Dopamine D3 Antagonists -- 2.7.14 Inhibitors of Soluble Epoxide Hydrolase (Tested in Mice, po) -- 2.7.15 Melanin-Concentrating Hormone Receptor-1 Antagonists -- References -- Part II The Pharmacokinetic Properties of Compound Classes -- 3 Alkanes -- 3.1 Metabolism -- References -- 4 Alkenes and Alkynes -- 4.1 Metabolism -- References -- 5 Arenes -- 5.1 Metabolism -- 6 Halides -- 6.1 Fluorine -- 6.2 Chlorine -- 6.3 Bromine -- 6.4 Iodine -- 6.5 Alkylating Agents -- Reference -- 7 Azides -- 8 Nitro Compounds -- 8.1 Metabolism -- 9 Azo Compounds -- 10 Triazenes -- 11 Nitrates and Nitrites -- Further Reading -- 12 N-Nitroso Compounds -- 13 N-Oxides -- 14 Alcohols -- 14.1 Metabolism -- 15 Phenols -- References -- 16 Ethers.

16.1 Metabolism -- Reference -- 17 Epoxides -- 18 Peroxides -- 19 Thiols -- 20 Thioethers -- 20.1 Metabolism -- Reference -- 21 Sulfoxides -- 22 Sulfones -- 23 Aliphatic Amines -- 23.1 Basicity -- 23.2 Metabolism -- 23.3 Rates of N-Dealkylation -- Reference -- 24 Quaternary Ammonium Salts -- Reference -- 25 Amidines -- Reference -- 26 Guanidines, Acylguanidines, and Biguanides -- 26.1 Acylguanidines -- 26.2 Biguanides -- Reference -- 27 Anilines -- 27.1 Metabolism -- 28 Hydrazines, Acylhydrazines, and Hydrazones -- 29 Aldehydes -- 30 Ketones -- 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 -- 32 Carboxylic Esters -- Reference -- 33 Amides -- 34 Lactams and Imides -- 34.1 Pyrazolone Antipyretics -- 34.2 Five-Membered Lactams as Nootropics -- References -- 35 Nitriles -- References -- 36 Carbonates -- 37 Carbamates -- 37.1 Carbamates as Hypnotics -- References -- 38 Ureas -- Reference -- 39 Thiocarbonyl Compounds -- 40 Sulfonic Acids -- 41 Sulfonic Esters -- 42 Sulfates and Sulfamic Acids -- 43 Phosphonic Acids -- 44 Phosphoric Acid Derivatives -- 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds -- Reference -- 46 Arylalkylamines -- 46.1 Antihistaminics: History -- Reference -- 47 Phenethylamines (2-Phenylethylamines) -- 47.1 Biological Activity of Phenethylamines -- 47.2 Metabolism -- 47.3 Tetrahydroisochinolines and Related Compounds -- Further Reading -- 48 Aminoalkylindoles and Indole Alkaloids -- Reference -- 49 Phenothiazines -- 49.1 Metabolism -- References -- 50 Dibenzazepines and Related Tricyclic Compounds -- 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists -- ''β-Blockers'') -- 51.1 Metabolism -- 52 Opiates -- Reference -- 53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils) -- Reference.

54 Anilides and Amides of Glycine -- 55 Peptides, Peptidomimetics, and Related Oligoamides -- 55.1 Peptidomimetics -- 55.2 Thrombin Inhibitors and Related Compounds -- References -- 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas -- References -- 57 Imidazoles -- References -- 58 Triazoles -- 59 Pyridines, Pyrimidines, and Related Compounds -- 59.1 Proton Pump Inhibitors -- References -- 60 Quinolines -- 60.1 Tecans -- 60.2 Quinazolines -- References -- 61 Nucleoside Analogs -- Reference -- 62 Dihydropyridines -- 63 Arenesulfonamides -- 63.1 Antibacterials -- 63.2 Diuretics -- Reference -- 64 Sulfonylureas -- 65 Benzodiazepines -- Reference -- 66 Steroids -- References -- 67 Anthracyclines -- 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDS) -- 68.1 Salicylates -- References -- 69 Quinolonecarboxylic Acids (Gyrase Inhibitors) -- 70 β-Lactams -- 70.1 Cephalosporins -- Reference -- 71 Prostaglandin Analogs -- 72 Sartans -- Reference -- 73 Statins -- 74 Folic Acid Analogs (Antifolates) -- 75 Taxanes -- Reference -- 76 Macrocyclic Compounds -- Reference -- Index.