pyrimidinones and pyrazole

A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Topics: Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidinones; Structure-Activity Relationship

We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amongst all the synthesized compounds, 6-methyl-5-(4-methylpyridin-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5k) was found to be the most active based on in vitro DPP-IV studies and also exhibited promising in vivo blood glucose lowering activity in male Wistar rats.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Drug Design; Hyperglycemia; Hypoglycemic Agents; Male; Models, Molecular; Molecular Structure; Pyrazoles; Pyrimidinones; Rats; Rats, Wistar; Structure-Activity Relationship