title: The discovery of potent antagonists of NPBWR1 (GPR7).
abstract: The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i).
authors.affiliation: Merck & Co., Inc., Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA. anthony_romero@merck.com
authors.forename: F
authors.initials: F
authors.lastname: Anthony Romero
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Hastings
authors.forename: Remond
authors.initials: R
authors.lastname: Moningka
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.forename: Ying
authors.initials: Y
authors.lastname: Lei
authors.forename: Dorina
authors.initials: D
authors.lastname: Trusca
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Vincent
authors.initials: V
authors.lastname: Tong
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Terebetski
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001596:Benzylamines; C485722:NPBWR1 protein, human; C485721:Npbwr1 protein, mouse; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D000077489:Piperazine; C030796:benzylamine