Abstract
ABSTRACT A series of pyrrole structure-based CB1 receptor ligands was constructed by the Paal-Knorr reaction. Pyrrole amides 72 and 96, which were substituted with (R)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl, exhibited high affinity and excellent selectivity for CB1 receptor (IC50 = 4.2 nM and 1.9 nM, respectively). The presence of cyclohexyl group on pyrrole amides 64 (IC50 = 15.2 nM) and 94 (IC50 = 14.3 nM) also showed promising binding affinity enhancement to CB1 receptor. Moreover, C3-carboxamides of pyrrole compounds substituted with terminal ethyne, which contain not only symmetric dialkyl group but also one long alkyl chain such as 75, 77, 79, and 80 demonstrated high CB1 binding affinity. These results suggested that pyrrole amides 41 and 42 might become candidates to provide physicochemical benefits towards CB1. Compound 104 (IC50 = 12.0 nM for CB1), a pyrazole derivative by replacement of rimonabant C-3 group with cyclohexylethynyl amide, shows the same affinity as rimonabant C-3 for CB1 receptor, indicating that terminal ethyne unit provides unusual enhancement of receptor-ligand interaction to inactivate CB1 receptor. Key Words: Rimonabant; Anti-Obesity agents; CB1-antagonists; Pyrrole; Metabolic syndrome therapy; receptor blockers