title: Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists.
abstract: A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Shuanghua
authors.initials: S
authors.lastname: Hu
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Yazhong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Milind
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Luo
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Bruce
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Mattson
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Iben
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Russell
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Clarke
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogan
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Astrid
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Oliver
authors.initials: O
authors.lastname: Flint
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Henwood
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Antal-Zimanyi
authors.affiliation: Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Poindexter
keywords: bicyclo[3.1.0]hexanylpiperazines; brain penetration; noncompetitive neuropeptide Y Y1 antagonists