title: Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. richard_isaacs@merck.com
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Isaacs
authors.forename: Mark G
authors.initials: MG
authors.lastname: Solinsky
authors.forename: Kellie J
authors.initials: KJ
authors.lastname: Cutrona
authors.forename: Christina L
authors.initials: CL
authors.lastname: Newton
authors.forename: Adel M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: E A
authors.initials: EA
authors.lastname: Lyle
mesh_terms: 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
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D002712:Chlorides; D005290:Ferric Compounds; D007093:Imidazoles; D014357:Trypsin; D013917:Thrombin; C024555:ferric chloride