title: Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist.
abstract: A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. guanglin.luo@bms.com
authors.forename: Guanglin
authors.initials: G
authors.lastname: Luo
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Shuanghua
authors.initials: S
authors.lastname: Hu
authors.forename: Yazhong
authors.initials: Y
authors.lastname: Huang
authors.forename: Gail
authors.initials: G
authors.lastname: Mattson
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Iben
authors.forename: John W
authors.initials: JW
authors.lastname: Russell
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Clarke
authors.forename: John B
authors.initials: JB
authors.lastname: Hogan
authors.forename: Ildiko
authors.initials: I
authors.lastname: Antal-Zimanyi
authors.forename: Graham S
authors.initials: GS
authors.lastname: Poindexter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D006571:Heterocyclic Compounds; D017476:Receptors, Neuropeptide Y; C046059:bicyclo(3.1.0)hexane