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Letter

Low Molecular Weight Activated Protein C Inhibitors as a Potential Treatment for Hemophilic Disorders

Supporting Info

Guillaume De Nanteuil,*^§ Philippe Gloanec,^§ Suzette Béguin,^# Peter L. A. Giesen,^# H. Coenraad Hemker,^# Philippe Mennecier,^† Alain Rupin,^† and Tony J. Verbeuren^†

Division D of Medicinal Chemistry and Division of Angiology, Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes, France, and Synapse b.v., Cardiovascular Research Institute Maastricht, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands

J. Med. Chem., 2006, 49 (17), pp 5047–5050

DOI: 10.1021/jm0606950

Publication Date (Web): July 25, 2006

To whom correspondence should be addressed. Phone: +33 1 55 72 22 34. Fax: +33 1 55 72 24 30. E-mail: guillaume.denanteuil@fr.netgrs.com.

Division D of Medicinal Chemistry, Institut de Recherches Servier.

University of Maastricht,.

†

Division of Angiology, Institut de Recherches Servier.

Abstract

The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.

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