Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles.
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Isaacs
Richard C A
RC
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. richard_isaacs@merck.com
Solinsky
Mark G
MG
Cutrona
Kellie J
KJ
Newton
Christina L
CL
Naylor-Olsen
Adel M
AM
McMasters
Daniel R
DR
Krueger
Julie A
JA
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Kuo
Lawrence C
LC
Yan
Youwei
Y
Lynch
J J
JJ
Lyle
E A
EA
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002712:Chlorides; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D005290:Ferric Compounds / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D010314:Partial Thromboplastin Time; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000925:Anticoagulants; D000991:Antithrombins; D002712:Chlorides; D005290:Ferric Compounds; D007093:Imidazoles; D014357:Trypsin; D013917:Thrombin; C024555:ferric chloride