Solid-phase optimisation of achiral amidinobenzyl indoles as potent and selective factor Xa inhibitors.

Starting from the achiral and potent factor Xa inhibitor 1, a new and flexible solid-phase optimisation strategy is described to reduce its cationic character. By replacing one positively charged side chain by a lipophilic substituent, a novel series of highly potent and selective achiral factor Xa inhibitors was discovered. The identified lipophilic replacements in the S4 pocket might be valuable for other approaches towards fXa inhibitors.

[1]  H. Ishihara,et al.  DX-9065a, an Orally Active, Specific Inhibitor of Factor Xa, Inhibits Thrombosis without Affecting Bleeding Time in Rats , 1995, Thrombosis and Haemostasis.

[2]  R. Schwesinger,et al.  Novel, Very Strong, Uncharged Auxiliary Bases; Design and Synthesis of Monomeric and Polymer‐Bound Triaminoiminophosphorane Bases of Broadly Varied Steric Demand , 1994 .

[3]  S. Hanson,et al.  Antithrombotic Benefits and Hemorrhagic Risks of Direct Thrombin Antagonists , 1995, Thrombosis and Haemostasis.

[4]  R. Huber,et al.  Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: implications for the inhibition of factor Xa, tPA, and urokinase. , 1998, Journal of medicinal chemistry.

[5]  R. Huber,et al.  Structure of human des(1-45) factor Xa at 2.2 A resolution. , 1993, Journal of molecular biology.

[6]  M. Whitlow,et al.  Synthesis, characterization, and structure-activity relationships of amidine-substituted (bis)benzylidene-cycloketone olefin isomers as potent and selective factor Xa inhibitors. , 1999, Journal of medicinal chemistry.

[7]  D. E. Smith,et al.  Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. , 1990, Science.

[8]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[9]  R. Engh,et al.  Tetrahydro-isoquinoline-based factor Xa inhibitors. , 1998, Journal of medicinal chemistry.

[10]  G. Wagner,et al.  Synthese von Nα-(Arylsulfonylglycyl)amidinophenylalaninamiden als hochaktive Inhibitoren des Thrombins , 1984 .

[11]  D. E. Patterson,et al.  Designing Chemical Libraries for Lead Discovery , 1996 .

[12]  N. Sepetov,et al.  Discovery of a novel, potent, and specific family of factor Xa inhibitors via combinatorial chemistry. , 1998, Biochemistry.

[13]  D L Cheney,et al.  Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. , 1999, Journal of medicinal chemistry.

[14]  R. Knabb,et al.  Preparation of pyrrolidine and isoxazolidine benzamidines as potent inhibitors of coagulation factor Xa. , 1999, Bioorganic & medicinal chemistry letters.

[15]  S. Brady,et al.  Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. , 1998, Journal of medicinal chemistry.

[16]  G. Rishton.  Reactive compounds and in vitro false positives in HTS , 1997 .

[17]  C. Marlowe,et al.  Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: structures based on the (D)-Arg-Gly-Arg tripeptide sequence. , 2000, Bioorganic & medicinal chemistry letters.

[18]  J R Pruitt,et al.  Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. , 1999, Journal of medicinal chemistry.

[19]  A. Spada,et al.  Amido-(propyl and allyl)-hydroxybenzamidines: development of achiral inhibitors of factor Xa. , 2000, Bioorganic & medicinal chemistry letters.