Syntheses and Selective Inhibitory Activities of Terphenyl‐Bisamidines for Serine Proteases

Biphenyl nitriles 5a—c , terphenyl dinitriles 11a—d , and naphthalene‐bis(benzonitrile) 11e were prepared by palladium‐catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a—c and bis(benzamidines) 4a—e. Among the biphenyl amidines 8 only the meta ‐derivative 8b inhibits factor Xa and trypsin ( K i = 10 μM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of theses enzymes ( K i 1–6 μM), and 4b and 4e are selective for trypsin ( K i = 0.2 and 0.3 μM; but K i > 1 μM for factor Xa, thrombin, and plasmin). X‐ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.