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 K(i) 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.
Lee
Koo
K
Life Science R&D, LGCI, PO Box 61 Yu-Sung, Science Town, Taejon 305-380, Republic of Korea.kleec@lgci.co.kr
Jung
Won-Hyuk
WH
Park
Cheol Won
CW
Park
Hee Dong
HD
Lee
Sun Hwa
SH
Kwon
O Hwan
OH
D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry* / Q000378:metabolism; D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000882:Haplorhini; D006490:Hemostatics / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000578:Amidines; D000588:Amines; D005343:Fibrinolytic Agents; D006490:Hemostatics; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin