Azaindoles: moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors.
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.
Sanderson
Philip E J
PE
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phil_sanderson@merck.com
Stanton
Matthew G
MG
Dorsey
Bruce D
BD
Lyle
Terry A
TA
McDonough
Colleen
C
Sanders
William M
WM
Savage
Kelly L
KL
Naylor-Olsen
Adel M
AM
Krueger
Julie A
JA
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Lynch
Joseph J
JJ
Yan
Youwei
Y
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
D001372:Aza Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D011725:Pyridines; D014357:Trypsin; D013917:Thrombin