title: Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide.
abstract: Thrombin, a crucial enzyme in the blood coagulation, has been a target for antithrombotic therapy. Orally active thrombin inhibitors would provide effective and safe prophylaxis for venous and arterial thrombosis. We conducted optimization of a highly efficacious benzamidine-based thrombin inhibitor LB30812 (3, K(i) = 3 pM) to improve oral bioavailability. Of a variety of arylamidines investigated at the P1 position, 2,5-thienylamidine effectively replaced the benzamidine without compromising the thrombin inhibitory potency and oral absorption. The sulfamide and sulfonamide derivatization at the N-terminal position in general afforded highly potent thrombin inhibitors but with moderate oral absorption, while the well-absorbable N-carbamate derivatives exhibited limited metabolic stability in S9 fractions. The present work culminated in the discovery of the N-carboxymethyl- and 2,5-thienylamidine-containing compound 22 that exhibits the most favorable profiles of anticoagulant and antithrombotic activities as well as oral bioavilability (K(i) = 15 pM; F = 43%, 42%, and 15% in rats, dogs, and monkeys, respectively). This compound on a gravimetric basis was shown to be more effective than a low molecular weight heparin, enoxaparin, in the venous thrombosis models of rat and rabbit. Compound 22 (LB30870) was therefore selected for further preclinical and clinical development.
authors.affiliation: LG Life Sciences Ltd./R&D Park, P.O. Box 61 Yu-Sung, Science Town, Taejon 305-380, Korea. kleec@lgls.co.kr
authors.forename: Koo
authors.initials: K
authors.lastname: Lee
authors.forename: Cheol Won
authors.initials: CW
authors.lastname: Park
authors.forename: Won-Hyuk
authors.initials: WH
authors.lastname: Jung
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Park
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyung Ha
authors.initials: KH
authors.lastname: Chung
authors.forename: Su Kyung
authors.initials: SK
authors.lastname: Park
authors.forename: O Hwan
authors.initials: OH
authors.lastname: Kwon
authors.forename: Myunggyun
authors.initials: M
authors.lastname: Kang
authors.forename: Doo-Hee
authors.initials: DH
authors.lastname: Park
authors.forename: Sang Koo
authors.initials: SK
authors.lastname: Lee
authors.forename: Eunice E
authors.initials: EE
authors.lastname: Kim
authors.forename: Suk Kyoon
authors.initials: SK
authors.lastname: Yoon
authors.forename: Aeri
authors.initials: A
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004355:Drug Stability; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005463:Fluoroacetates; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*; D020246:Venous Thrombosis / Q000188:drug therapy
chemical_list: D000578:Amidines; D000925:Anticoagulants; D004151:Dipeptides; D005343:Fibrinolytic Agents; D005463:Fluoroacetates; C476981:N-aminosulfonyldiphenylalanyl-prolyl-((4-amidinophenyl)methyl)amide; D011480:Protease Inhibitors; D013424:Sulfanilamides; C116659:thienylamidine; D013917:Thrombin