| Literature DB >> 24900458 |
Shuanghua Hu1, Yazhong Huang1, Milind Deshpande1, Guanglin Luo1, Marc A Bruce1, Ling Chen1, Gail Mattson1, Lawrence G Iben1, Jie Zhang1, John W Russell1, Wendy J Clarke1, John B Hogan1, Astrid Ortiz1, Oliver Flint1, Andrew Henwood1, Qi Gao1, Ildiko Antal-Zimanyi1, Graham S Poindexter1.
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.Entities:
Keywords: bicyclo[3.1.0]hexanylpiperazines; brain penetration; noncompetitive neuropeptide Y Y1 antagonists
Year: 2012 PMID： 24900458 PMCID： PMC4025839 DOI： 10.1021/ml200265m
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345