title: Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1.
abstract: 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.
authors.affiliation: Life Science R&D, LGCI, PO Box 61 Yu-Sung, Science Town, Taejon 305-380, Republic of Korea.kleec@lgci.co.kr
authors.forename: Koo
authors.initials: K
authors.lastname: Lee
authors.forename: Won-Hyuk
authors.initials: WH
authors.lastname: Jung
authors.forename: Cheol Won
authors.initials: CW
authors.lastname: Park
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Park
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: O Hwan
authors.initials: OH
authors.lastname: Kwon
mesh_terms: 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
chemical_list: D000578:Amidines; D000588:Amines; D005343:Fibrinolytic Agents; D006490:Hemostatics; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin