Design and Synthesis of Thrombin Inhibitors: Analogues of MD-805 with Reduced Stereogenicity and Improved Potency
| Autor: | Graham Arton Howarth, Talbot, Judy Hayler, Garrick Smith, Derek E. Brundish, Wakeford R, John Ambler, Mark C. Allen, Joseph D. Fullerton, Peter D. Kane, Christoph Walker, Sheila Garman, Donovan, Bull A, K D Butler, William Hoyle, Diana Janus, McDonnell M |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Stereochemistry medicine.drug_class Injections Subcutaneous Carboxamide Arginine Chemical synthesis Antithrombins Stereocenter Structure-Activity Relationship Thrombin Piperidines Drug Discovery medicine Animals Humans Potency Sulfonamides biology Chemistry Enantioselective synthesis Stereoisomerism Thrombosis Rats Enzyme inhibitor Drug Design Pipecolic Acids Injections Intravenous biology.protein Molecular Medicine Cattle medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 42:4584-4603 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|