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

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.

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