Autor: |
Van Huis CA, Bigge CF, Casimiro-Garcia A, Cody WL, Dudley DA, Filipski KJ, Heemstra RJ, Kohrt JT, Narasimhan LS, Schaum RP, Zhang E, Bryant JW, Haarer S, Janiczek N, Leadley RJ Jr, McClanahan T, Thomas Peterson J, Welch KM, Edmunds JJ |
Jazyk: |
angličtina |
Zdroj: |
Chemical biology & drug design [Chem Biol Drug Des] 2007 Jun; Vol. 69 (6), pp. 444-50. |
DOI: |
10.1111/j.1747-0285.2007.00520.x |
Abstrakt: |
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. |
Databáze: |
MEDLINE |
Externí odkaz: |
|