title: Diarylamidine derivatives with one or both of the aryl moieties consisting of an indole or indole-like ring. Inhibitors of arginine-specific esteroproteases.
abstract: A series of 62 diarylamidine derivatives was evaluated for their antiproteolytic activity. In all but two of the compounds one or both of the amidino-substituted aryl moieties was either an indole or an indole-like ring. The latter included indene, benzimidazole, benzofuran, benzol[beta]thiophene, and several other related nitrogen-containing heterocycles. Several of the compounds exhibited considerable inhibitory potency against thrombin, trypsin, and pancreatic kallikrein. An outstanding inhibitor of trypsin was found in bis(5-amidino-2-benzimidazolyl)methane (compound 42) with a Ki value of 1.7 X 10(-8) M(pH. 8.1, 37 degrees C). Another derivative, 1,2-di(4-amidino-2-benzofuranyl)ethane (compound 21), proved to be a highly effective inhibitor of the overall blood clotting process. From a general structure-activity standpoint these compounds demonstrate that minor structural variations of low-molecular-weight inhibitors can result in significant changes in specificity and potency with regard to antiproteolytic activity.
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000925:Anticoagulants / Q000138:chemical synthesis; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology; D001780:Blood Coagulation Tests; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007610:Kallikreins / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D013925:Thromboplastin; D013997:Time Factors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis
chemical_list: D000578:Amidines; D000925:Anticoagulants; D001562:Benzimidazoles; D001572:Benzofurans; D007211:Indoles; D011480:Protease Inhibitors; D013876:Thiophenes; D014361:Trypsin Inhibitors; D013925:Thromboplastin; D007610:Kallikreins; D013917:Thrombin