title: Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists.
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.
authors.affiliation: Department of Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics, Groton, CT 06340, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Blum
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Lombaert
authors.forename: John K
authors.initials: JK
authors.lastname: Inthavongsay
authors.forename: Lee E
authors.initials: LE
authors.lastname: Klade
authors.forename: Christine M
authors.initials: CM
authors.lastname: Mack
authors.forename: Colin R
authors.initials: CR
authors.lastname: Rose
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sanders
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D055808:Drug Discovery; D004435:Eating / Q000187:drug effects*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047069:Pyrazolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*
chemical_list: D001067:Appetite Depressants; C560207:CP 671906; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011743:Pyrimidines; D017476:Receptors, Neuropeptide Y