SYNTHESES AND SELECTIVE INHIBITORY ACTIVITIES OF TERPHENYL-BISAMIDINES FOR SERINE PROTEASES

Biphenyl nitriles 5a-c, terphenyl dinitriles 11a-d, and naphthalene-bi s(benzonitrile) 11e were prepared by palladium-catalyzed cross couplin g reactions and subsequently converted to biphenyl amidines 8a-c and b is(benzamidines) 4a-e. Among the biphenyl amidines 8 only the meta-der ivative 8b inhibits factor Xa and trypsin (K-i = 10 mu M). The terphen yl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and pl asmin, while 4a and 4d are almost equipotent inhibitors of these enzym es (K-i 1-6 mu M), and 4b and 4e are selective for trypsin (K-i = 0.2 and 0.3 mu M; but K-i > 1 mu M for factor Xa, thrombin, and plasmin). X-ray analysis of crystals of 4b complexed with bovine trypsin reveale d a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twi sted away from the S2/S3 sites and the second amidino group contacts t he Asn143 side chain.