title: Syntheses and selective inhibitory activities of terphenyl-bisamidines for serine proteases.
abstract: Biphenyl nitriles 5a-c, terphenyl dinitriles 11a-d, and naphthalene-bis(benzonitrile) 11c 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 (Ki = 10 microM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of these enzymes (Ki 1-6 microM), and 4b and 4e are selective for trypsin (Ki = 0.2 and 0.3 microM; but Ki > 1 microM 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.
authors.affiliation: Chemical Research Department, Boehringer Mannheim, Germany.
authors.forename: W
authors.initials: W
authors.lastname: von der Saal
authors.forename: R A
authors.initials: RA
authors.lastname: Engh
authors.forename: A
authors.initials: A
authors.lastname: Eichinger
authors.forename: B
authors.initials: B
authors.lastname: Gabriel
authors.forename: R
authors.initials: R
authors.lastname: Kucznierz
authors.forename: J
authors.initials: J
authors.lastname: Sauer
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000578:Amidines; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors