Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists.

Abstract Syntheses and structure–activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3 H ),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole ( 2r : IC 50  = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole ( 2u : IC 50  = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.