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 IC 50 = 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.

Transition-Metal-Free Synthesis of Tertiary Aminocyclopropanes

“…The aminocyclopropane motif is a key pharmacophore present in numerous natural products and a wide variety of biologically active pharmaceuticals . Such compounds include the phytotoxin coronatine ( I , Figure ), the FDA-approved dipeptidyl peptidase IV inhibitor saxagliptin ( II ) used in the treatment of type 2 diabetes, the Hepatitis C Virus NS3/4A protease inhibitor danoprevir ( III ), and the preclinical NPY1 antagonist IV …”