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L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 1998 Apr 07; Vol. 8 (7), pp. 817-22. - Publication Year :
- 1998
-
Abstract
- Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.
- Subjects :
- Administration, Oral
Animals
Anticoagulants administration & dosage
Anticoagulants chemistry
Biological Availability
Chlorides
Crystallography, X-Ray
Dogs
Ferric Compounds
Kinetics
Macaca fascicularis
Models, Molecular
Molecular Structure
Pyridones administration & dosage
Pyridones chemistry
Rats
Structure-Activity Relationship
Sulfonamides administration & dosage
Sulfonamides chemistry
Thrombosis drug therapy
Trypsin metabolism
Anticoagulants pharmacology
Pyridones pharmacology
Sulfonamides pharmacology
Thrombin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 8
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 9871547
- Full Text :
- https://doi.org/10.1016/s0960-894x(98)00117-6