title: Azaindoles: moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors.
abstract: Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phil_sanderson@merck.com
authors.forename: Philip E J
authors.initials: PE
authors.lastname: Sanderson
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: Colleen
authors.initials: C
authors.lastname: McDonough
authors.forename: William M
authors.initials: WM
authors.lastname: Sanders
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Savage
authors.forename: Adel M
authors.initials: AM
authors.lastname: Naylor-Olsen
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: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D010314:Partial Thromboplastin Time; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D011725:Pyridines; D014357:Trypsin; D013917:Thrombin