Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors

  • Chem Biol Drug Des. 2007 Jun;69(6):444-50. doi: 10.1111/j.1747-0285.2007.00520.x.
Chad A Van Huis ,  Christopher F Bigge ,  Agustin Casimiro-Garcia ,  Wayne L Cody ,  Danette A Dudley ,  Kevin J Filipski ,  Ronald J Heemstra ,  Jeffrey T Kohrt ,  Lakshmi S Narasimhan ,  Robert P Schaum ,  Erli Zhang ,  John W Bryant ,  Staci Haarer ,  Nancy Janiczek ,  Robert J Leadley Jr ,  Thomas McClanahan ,  J Thomas Peterson ,  Kathleen M Welch ,  Jeremy J Edmunds
PMID: 17581239 DOI: 10.1111/j.1747-0285.2007.00520.x
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.

Products