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

• Published in: Journal of medicinal chemistry 2003-08, Vol.46 (17), p.3612-3622
• Main Authors: Lee, Koo, Park, Cheol Won, Jung, Won-Hyuk, Park, Hee Dong, Lee, Sun Hwa, Chung, Kyung Ha, Park, Su Kyung, Kwon, O Hwan, Kang, Myunggyun, Park, Doo-Hee, Lee, Sang Koo, Kim, Eunice E, Yoon, Suk Kyoon, Kim, Aeri
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amidines - chemical synthesis; Amidines - pharmacokinetics; Amidines - pharmacology; Animals; Anticoagulants - chemical synthesis; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Dipeptides - chemical synthesis; Dipeptides - pharmacokinetics; Dipeptides - pharmacology; Dogs; Drug Stability; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Haplorhini; Humans; In Vitro Techniques; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfanilamides - chemical synthesis; Sulfanilamides - pharmacokinetics; Sulfanilamides - pharmacology; Thrombin - antagonists & inhibitors; Venous Thrombosis - drug therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030025j

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.