title: Tricyclic imidazole antagonists of the Neuropeptide S Receptor.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA. bwesley_trotter@merck.com
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: Cindra L
authors.initials: CL
authors.lastname: Condra
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Karsten
authors.initials: K
authors.lastname: Menzel
authors.forename: Martin
authors.initials: M
authors.lastname: Henault
authors.forename: Rino
authors.initials: R
authors.lastname: Stocco
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
mesh_terms: 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
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D018013:Receptors, Neuropeptide; C029899:imidazole