Jeffrey T Kohrt,
Kevin J Filipski,
Wayne L Cody,
Christopher F Bigge,
Frances La,
Kathleen Welch,
Tawny Dahring,
John W Bryant, Daniele Leonard,
Gary Bolton, [......],
Nancy Janiczek,
Shrilakshmi Desiraju,
Mostofa Hena,
Charles Fiakpui,
Neerja Saraswat,
Raman Sharma,
Shaoyi Sun,
Samarendra N Maiti,
Robert Leadley,
Jeremy J Edmunds
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ABSTRACT: Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Bioorganic & Medicinal Chemistry 08/2006; 14(13):4379-92. · 2.92 Impact Factor
