Tetrahydroindolizinone NK1 antagonists.
A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
Bao
Jianming
J
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. bao_jianming@merck.com
Lu
Huagang
H
Morriello
Gregori J
GJ
Carlson
Emma J
EJ
Wheeldon
Alan
A
Chicchi
Gary G
GG
Kurtz
Marc M
MM
Tsao
Kwei-Lan C
KL
Zheng
Song
S
Tong
Xinchun
X
Mills
Sander G
SG
DeVita
Robert J
RJ
D000818:Animals; D005849:Gerbillinae; D006801:Humans; D007212:Indolizines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007212:Indolizines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1