Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist

Guanglin Luo; Ling Chen; Shuanghua Hu; Yazhong Huang; Gail Mattson; Lawrence G Iben; John W Russell; Wendy J Clarke; John B Hogan; Ildiko Antal-Zimanyi; Graham S Poindexter

doi:10.1016/j.bmcl.2013.04.095

Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist

Bioorg Med Chem Lett. 2013 Jul 1;23(13):3814-7. doi: 10.1016/j.bmcl.2013.04.095. Epub 2013 May 15.

Authors

Guanglin Luo¹, Ling Chen, Shuanghua Hu, Yazhong Huang, Gail Mattson, Lawrence G Iben, John W Russell, Wendy J Clarke, John B Hogan, Ildiko Antal-Zimanyi, Graham S Poindexter

Affiliation

¹ Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. guanglin.luo@bms.com

PMID: 23726344
DOI: 10.1016/j.bmcl.2013.04.095

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.

MeSH terms

Administration, Oral
Animals
Bridged Bicyclo Compounds / administration & dosage
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology*
Dose-Response Relationship, Drug
Heterocyclic Compounds / administration & dosage
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Male
Molecular Structure
Rats
Rats, Sprague-Dawley
Receptors, Neuropeptide Y / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds
Heterocyclic Compounds
Receptors, Neuropeptide Y
bicyclo(3.1.0)hexane