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

Michael Fichtner; Eunsun Lee; Elizabeth Tomlinson; Dennis Scott; Peter Cornelius; Terrell A Patterson; Philip A Carpino

doi:10.1016/j.bmcl.2012.02.098

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. Epub 2012 Mar 6.

Authors

Michael Fichtner¹, Eunsun Lee, Elizabeth Tomlinson, Dennis Scott, Peter Cornelius, Terrell A Patterson, Philip A Carpino

Affiliation

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.

MeSH terms

Animals
Anti-Obesity Agents* / chemistry
Anti-Obesity Agents* / pharmacology
Cyclohexanes / pharmacology
Disease Models, Animal
Drug Discovery*
Drug Stability
Humans
Microsomes, Liver / drug effects
Molecular Structure
Protein Binding / drug effects
Pyrazoles / pharmacology
Rats
Receptors, Neuropeptide Y / antagonists & inhibitors*
Spiro Compounds / chemical synthesis*
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*

Substances

Anti-Obesity Agents
Cyclohexanes
Pyrazoles
Receptors, Neuropeptide Y
Spiro Compounds
neuropeptide Y5 receptor
spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-