Synthesis of conformationally constrained 5,6,7, 8-Tetrahydroimidazo[1,5-a]pyridine inhibitors of farnesyltransferase.
[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.
Dinsmore
C J
CJ
Departments of Medicinal Chemistry, Cancer Research, and Drug Metabolism, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA.
Zartman
C B
CB
Baginsky
W F
WF
O'Neill
T J
TJ
Koblan
K S
KS
Chen
I W
IW
McLoughlin
D A
DA
Olah
T V
TV
Huff
J R
JR
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051231:Farnesyltranstransferase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007202:Indicators and Reagents; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase