Dihydropyridine neuropeptide Y Y1 receptor antagonists 2: bioisosteric urea replacements

Abstract Structure–activity studies around the urea linkage in BMS-193885 ( 4a ) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y 1 receptor antagonists. In comparison to urea 4a ( K i =3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y 1 receptor ( K i =5.1 nM) and full functional antagonism ( K b =2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).