Tricyclic imidazole antagonists of the Neuropeptide S Receptor.
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.
Trotter
B Wesley
BW
Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA. bwesley_trotter@merck.com
Nanda
Kausik K
KK
Manley
Peter J
PJ
Uebele
Victor N
VN
Condra
Cindra L
CL
Gotter
Anthony L
AL
Menzel
Karsten
K
Henault
Martin
M
Stocco
Rino
R
Renger
John J
JJ
Hartman
George D
GD
Bilodeau
Mark T
MT
D000818:Animals; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D018013:Receptors, Neuropeptide; C029899:imidazole