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Structure‐based Drug Design of Pyrrolidine‐1, 2‐dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors
Author(s) -
Van Huis Chad A.,
Bigge Christopher F.,
CasimiroGarcia Agustin,
Cody Wayne L.,
Dudley Danette A.,
Filipski Kevin J.,
Heemstra Ronald J.,
Kohrt Jeffrey T.,
Narasimhan Lakshmi S.,
Schaum Robert P.,
Zhang Erli,
Bryant John W.,
Haarer Staci,
Janiczek Nancy,
Leadley Robert J.,
McClanahan Thomas,
Thomas Peterson J.,
Welch Kathleen M.,
Edmunds Jeremy J.
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00520.x
Subject(s) - bioavailability , pyrrolidine , chemistry , drug , pharmacology , drug design , stereochemistry , biochemistry , medicine
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 n m ). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa ( 13 , IC 50 = 0.38 n m ), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.