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.
Morriello
Gregori J
GJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. greg_morriello@merck.com
Mills
Sander G
SG
Johnson
Tricia
T
Reibarkh
Mikhail
M
Chicchi
Gary
G
DeMartino
Julie
J
Kurtz
Marc
M
Davies
P
P
Tsao
K L C
KL
Zheng
Song
S
Tong
Xinchun
X
Carlson
Emma
E
Townson
Karen
K
Tattersall
F D
FD
Wheeldon
Alan
A
Boyce
Susan
S
Collinson
Neil
N
Rupniak
Nadia
N
Moore
Stephen
S
DeVita
Robert J
RJ
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