ABSTRACT
1-Aryl-3-carboxamido-5-alkylpyrazoles were prepared based on a hit found in high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. 1-(3-Trifluoromethylphenyl)-3-[N-(5-quinolinyl)carboxamido]-5-methylpyrazole (31) bound to the human neuropeptide Y5 receptor with a 80 nM IC(50 )and was shown to inhibit cumulative food consumption 43.2% 2-6 h after ip dosing in a fasting-induced feeding model in rats.
Subject(s)
Eating/drug effects , Isoquinolines/chemistry , Isoquinolines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, Neuropeptide Y/metabolism , Animals , Drug Evaluation, Preclinical/methods , Fasting , Humans , Inhibitory Concentration 50 , Ligands , Male , Rats , Rats, Long-Evans , Receptors, Neuropeptide Y/drug effects , Structure-Activity RelationshipABSTRACT
1,3-Disubstituted-5-aminopyrazoles were prepared based on a lead compound found through high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. The target compounds were prepared by cyclization of alpha-cyanoketones with appropriate hydrazines, followed by reduction and coupling to various sulfonamido-carboxylic acids. Several of these arylpyrazoles (e.g., 19 and 45) displayed high affinity for the human NPY Y5 receptor (<20nM IC(50)s).