Dörwald F.Z. Lead optimization for medicinal chemists: pharmacokinetic properties of functional groups and organic compounds. - Weinheim: Wiley-VCH, 2012. - xvi, 605 p.: ill. - Ind.: p.567-605. - ISBN 978-3-527-33226-7  Место хранения:   032 | Институт органической химии им. Н.Н.Ворожцова СО РАН | Новосибирск | Библиотека

Оглавление / Contents

Introduction .............................................. ХIII Glossary and Abbreviations .................................. XV Part I Introduction ......................................... 1 1 The Drug Discovery Process ................................... 3 1.1 Pharmacokinetics-Structure Relationship ................. 5 1.2 The Future of S mall-Molecule Drags ..................... 9 References .................................................. 11 2 Lead Optimization ........................................... 13 2.1 What Limits/Reduces Oral Bioavailability? .............. 14 2.2 What Limits/Reduces Plasma Half-Life? .................. 15 2.3 How to Improve bbb-Penetration? ........................ 16 2.4 How to Avoid CYP Inhibition/Induction? ................. 16 2.5 How to Avoid Interaction with the Human Ether-à-go-go-Related Gene (hERG)? ..................... 17 2.6 How to Prevent Toxicity? ............................... 17 2.7 Examples of PK-Optimization in Animals ................. 20 2.7.1 Dihydroorotate Dehydrogenase Inhibitors ......... 20 2.7.2 Matrix Metalloproteinase Inhibitors ............. 21 2.7.3 Antibacterial Aminobenzenesulfonamides .......... 21 2.7.4 Tyrosine Kinase Inhibitors ...................... 22 2.7.5 5-HT1A Agonists ................................. 23 2.7.6 Dipeptidyl Peptidase IV Inhibitors; Structural Variations of Sitagliptin ....................... 23 2.7.7 P-Selectin Inhibitors ........................... 24 2.7.8 β3-Adrenergic Agonists .......................... 24 2.7.9 Vanilloid-1 Antagonists ......................... 25 2.7.10 HIV Protease Inhibitors ......................... 25 2.7.11 Matrix Metalloproteinase Inhibitors (Tested in Rats) ........................................... 26 2.7.12 HIV Integrase Inhibitors ........................ 26 2.7.13 Dopamine D3 Antagonists ......................... 27 2.7.14 Inhibitors of Soluble Epoxide Hydrolase (Tested in Mice, po) ............................ 28 2.7.15 Melanin-Concentrating Hormone Receptor-1 Antagonists ..................................... 29 References ............................................. 29 Part II The Pharmacokinetic Properties of Compound Classes ..... 33 3 Alkanes ..................................................... 35 3.1 Metabolism ............................................. 36 References .................................................. 39 4 Alkenes and Alkynes ......................................... 40 4.1 Metabolism ............................................. 40 References .................................................. 44 5 Arenes ...................................................... 45 5.1 Metabolism ............................................. 45 6 Halides ..................................................... 49 6.1 Fluorine ............................................... 49 6.2 Chlorine ............................................... 51 6.3 Bromine ................................................ 53 6.4 Iodine ................................................. 53 6.5 Alkylating Agents ...................................... 54 Reference ................................................... 55 7 Azides ...................................................... 58 8 Nitro Compounds .......................................... 59 8.1 Metabolism ............................................. 60 9 Azo Compounds ............................................... 62 10 Triazenes ................................................... 64 11 Nitrates and Nitrites ....................................... 66 Further Reading ............................................. 67 12 N-Nitroso Compounds ......................................... 68 13 N-Oxides .................................................... 70 14 Alcohols .................................................... 71 14.1 Metabolism ............................................. 72 15 Phenols ..................................................... 82 References .................................................. 84 16 Ethers ...................................................... 91 16.1 Metabolism ............................................. 92 Reference ................................................... 93 17 Epoxides .................................................... 96 18 Peroxides ................................................... 97 19 Thiols ...................................................... 98 20 Thioethers ................................................. 100 20.1 Metabolism ............................................ 101 Reference .................................................. 103 21 Sulfoxides ................................................. 104 22 Sulfones ................................................... 106 23 Aliphatic Amines ........................................... 107 23.1 Basicity .............................................. 130 23.2 Metabolism ............................................ 110 23.3 Rates of N-Dealkylation ............................... 112 Reference .................................................. 114 24 Quaternary Ammonium Salts .................................. 118 Reference .................................................. 119 25 Amidines ................................................... 120 Reference .................................................. 121 26 Cuanidines, Acylguanidines, and Biguanides ................. 122 26.1 Acylguanidines ........................................ 123 26.2 Biguanides ............................................ 123 Reference .................................................. 124 27 Anilines ................................................... 133 27.1 Metabolism ............................................ 135 28 Hydrazines, Acylhydrazines, and Hydrazones ................. 137 29 Aldehydes .................................................. 138 30 Ketones .................................................... 139 31 Carboxylic Acids ........................................... 144 31.1 Metabolism ............................................ 145 31.2 Bioisosteres of Carboxylic Acids ...................... 146 31.3 Amino Carboxylic Acids, N-Acyl Amino Acids, and Related Compounds ..................................... 147 References ................................................. 348 32 Carboxylic Esters .......................................... 164 Reference .................................................. 165 33 Amides ..................................................... 366 34 Lactams and Imides ......................................... 172 34.1 Pyrazolone Antipyretics ............................... 372 34.2 Five-Membered Lactams as Nootropics ................... 173 References ................................................. 374 35 Nitriles ................................................... 384 References ................................................. 185 36 Carbonates ................................................. 186 37 Carbamates ................................................. 387 37.1 Carbamates as Hypnotics ............................... 388 References ................................................. 389 38 Ureas ...................................................... 392 Reference .................................................. 393 39 Thiocarbonyl Compounds ..................................... 201 40 Sulfonic Acids ............................................. 203 41 Sulfonic Esters ............................................ 206 42 Sulfates and Sulfamic Acids ................................ 207 43 Phosphonic Acids ........................................... 209 44 Phosphoric Acid Derivatives ................................ 213 45 N-(Aminoalkyl)benzamides, -Benzoates, and Related Compounds .................................................. 215 Reference .................................................. 216 46 Arylalkylamines ............................................ 225 46.1 Antihistaminics: History .............................. 225 Reference .................................................. 226 47 Phenethylamines (2-Phenylethylamines) ...................... 267 47.1 Biological Activity of Phenethylamines ................ 267 47.2 Metabolism ............................................ 268 47.3 Tetrahydroisochinolines and Related Compounds ......... 269 Further Reading ............................................ 270 48 Aminoalkylindoles and Indole Alkaloids ..................... 291 Reference .................................................. 291 49 Phenothiazines ............................................. 301 49.1 Metabolism ............................................ 302 References ................................................. 302 50 Dibenzazepines and Related Tricyclic Compounds ............. 310 51 3-Aryloxy-2-Hydroxypropylamines (β-Adrenergic Antagonists; β-Blockers") .................................. 320 51.1 Metabolism ............................................ 320 52 Opiates .................................................... 329 Reference .................................................. 329 53 N-(Carboxyalkyl)-α-Amino Acid Amides (Prils) ............... 335 Reference .................................................. 336 54 Anilides and Amides of Glycine ............................. 341 55 Peptides, Peptidomimetics, and Related Oligoamides ......... 347 55.1 Peptidomimetics ....................................... 348 55.2 Thrombin Inhibitors and Related Compounds ............. 349 References ............................................ 350 56 Oligoarylamines, Oligoarylamides, Oligoarylcarbamates, and Oligoarylureas ......................................... 365 References ................................................. 365 57 Imidazoles ................................................. 377 References ................................................. 378 58 Triazoles .................................................. 387 59 Pyridines, Pyrimidines, and Related Compounds .............. 393 59.1 Proton Pump Inhibitors ................................ 396 References ................................................. 397 60 Quinolines ................................................. 412 60.1 Tecans ................................................ 415 60.2 Quinazolines .......................................... 415 References ................................................. 416 61 Nucleoside Analogs ......................................... 428 Reference .................................................. 428 62 Dihydropyridines ........................................... 446 63 Arenesulfonamides .......................................... 450 63.1 Antibacterials ........................................ 450 63.2 Diuretics ............................................. 450 Reference .................................................. 451 64 Sulfonylureas .............................................. 462 65 Benzodiazepines ............................................ 466 Reference .................................................. 467 66 Steroids ................................................... 477 References ................................................. 478 67 Anthracyclines ............................................. 492 68 Arylacetic, Benzoic, and Related Carboxylic Acids (NSAIDS) ................................................... 497 68.1 Salicylates ........................................... 497 References ................................................. 498 69 Quinolonecarboxylic Acids (Cyrase Inhibitors) .............. 514 70 P-Lactams .................................................. 522 70.1 Cephalosporins ........................................ 523 Reference .................................................. 523 71 Prostaglandin Analogs ...................................... 538 72 Sartans .................................................... 543 Reference .................................................. 544 73 Statins .................................................... 548 74 Folic Acid Analogs (Antifolates) ........................... 551 75 Taxanes .................................................... 554 Reference .................................................. 554 76 Macrocyclic Compounds ...................................... 557 Reference .................................................. 557 Index ...................................................... 567