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Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2007 Jun; Vol. 69 (6), pp. 444-50. - Publication Year :
- 2007
-
Abstract
- A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
- Subjects :
- Administration, Oral
Animals
Antithrombin III pharmacology
Crystallization
Dogs
Drug Design
Humans
Inhibitory Concentration 50
Models, Chemical
Models, Molecular
Protein Binding
Pyrrolidonecarboxylic Acid chemistry
Structure-Activity Relationship
Time Factors
Antithrombin III chemistry
Chemistry, Pharmaceutical methods
Pyrrolidonecarboxylic Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0277
- Volume :
- 69
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Editorial & Opinion
- Accession number :
- 17581239
- Full Text :
- https://doi.org/10.1111/j.1747-0285.2007.00520.x