280781-39-7

Upstream product

• 172349-09-6 5-(hydroxymethyl)thiophene-2-carbonitrile 
• 79387-71-6 (5-bromothien-2-yl)methanol 
• 4701-17-1 5-bromo-2-thiophencarboxaldehyde 
• 201799-21-5 5-(N,N-Boc₂-aminomethyl)thiophene-2-carbonitrile 
• 134135-41-4 5-(bromomethyl)thiophene-2-carbonitrile 
• 72835-25-7 2-cyano-5-methylthiophene 
• 765-58-2 2-bromo-5-methyl thiophene 
• 138971-65-0 N-(tert-butyloxycarbonyl)-D-3,3-diphenylalanyl-L-proline 
• 172349-10-9 5-(aminomethyl)thiophene-2-carbonitrile hydrochloride 
• 227279-10-9 2-cyano-5-(aminomethyl)thiophene 

Downstream Products

• 280781-55-7 N-(tert-butoxycarbonyl)methyl-D-diphenylalanyl-L-prolyl[(5-hydroxyamidino-2-thienyl)methyl]amide 
• 280780-95-2 2-{[(1R)-2-((2S)-2{[({5-[amino(imino)methyl]-2-thienyl}methyl)amino]carbonyl}-pyrrolidinyl)-1-benzhydryl-2-oxoethyl]amino}acetic acid 
• 280781-82-0 N-[2-(methoxycarbonyl)ethyl]-D-diphenylalanyl-L-propyl[(5-cyano-2-thienyl)methyl]amide 

Relevant academic research and scientific papers

PEPTIDIC THROMBIN INHIBITOR COMPOUND

The present invention relates to a novel thrombin inhibitor compound which has a good inhibitory effect against thrombosis and can be orally administered, a process for preparing the same, and to a composition for the therapeutic and/or prophylactic treatment of various diseases associated with thrombin inhibition mechanism, which comprises the same as an active ingredient.

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)methyllamide

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, Ki = 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 (Ki = 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.

Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1

A series of noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1 was investigated. While the amidrazone and the amine series displayed limited oral absorption, the amidine series demonstrated generally good oral absorption and strong antithrombotic activity; the single-digit picomolar Ki achieved from this series is among the best yet reported. The present work highlights the benzamidine compound 11f (LB30812) that exhibits excellent overall profiles of potency, oral absorption and antithrombotic efficacy.