SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa

…, S Wang, S Nakajima, KA Rossi, A Smallwood…

Index: Smallheer, Joanne M.; Alexander, Richard S.; Wang, Jianmin; Wang, Shuaige; Nakajima, Suanne; Rossi, Karen A.; Smallwood, Angela; Barbera, Frank; Burdick, Debra; Luettgen, Joseph M.; Knabb, Robert M.; Wexler, Ruth R.; Jadhav, Prabhakar K. Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, # 21 p. 5263 - 5267

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Citation Number: 37

Abstract

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5–10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.