Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor

  • Bioorg Med Chem Lett. 2012 Apr 15;22(8):2738-43. doi: 10.1016/j.bmcl.2012.02.098.
Michael Fichtner  1 ,  Eunsun Lee ,  Elizabeth Tomlinson ,  Dennis Scott ,  Peter Cornelius ,  Terrell A Patterson ,  Philip A Carpino
Affiliations
  • 1. Department of Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics, Groton, CT 06340, USA.
PMID: 22445286 DOI: 10.1016/j.bmcl.2012.02.098
Abstract

A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s ≤ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period.

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