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Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists |
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| Authors: | Griffith David A Hargrove Diane M Maurer Tristan S Blum Charles A De Lombaert Stéphane Inthavongsay John K Klade Lee E Mack Christine M Rose Colin R Sanders Martin J Carpino Philip A |
| Affiliation: | a Department of Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics, Groton, CT 06340, USA b Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research & Development, Groton, CT 06340, USA c Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer PharmaTherapeutics, Groton, CT 06340, USA d Neurogen Corporation, Branford, CT 06405, USA |
| Abstract: | A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents. |
| Keywords: | Obesity NPY Y1R Pyrazolo[1,5-a]pyrimidine |
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