Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists.
Previous work on human NK(1) (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK(1) antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24h with ID(50)'s of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. greg_morriello@merck.com
Gregori J
GJ
Morriello
Sander G
SG
Mills
Tricia
T
Johnson
Mikhail
M
Reibarkh
Gary
G
Chicchi
Julie
J
DeMartino
Marc
M
Kurtz
P
P
Davies
K L C
KL
Tsao
Song
S
Zheng
Xinchun
X
Tong
Emma
E
Carlson
Karen
K
Townson
F D
FD
Tattersall
Alan
A
Wheeldon
Susan
S
Boyce
Neil
N
Collinson
Nadia
N
Rupniak
Stephen
S
Moore
Robert J
RJ
DeVita
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles