SYNTHESIS AND EVALUATION OF A SERIES OF NOVEL 2-[(4-CHLOROPHENOXY)METHYL]BENZIMIDAZOLES AS SELECTIVE NEUROPEPTIDE-Y Y1 RECEPTOR ANTAGONISTS

A series of novel benzimidazoles (BI) derived from the indole 2 was sy nthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR a pproach, the (4-chlorophenoxy)methyl group at C-2 was kept constant an d a series of BIs substituted with various piperidinylalkyl groups at N-1 was synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen relative to the benzimidazole. The 3-(3- piperidinyl)propyl in 33 was found to maximize affinity for the Y1 rec eptor. Because of the critical importance of Arg(33) and Arg(35) Of NP Y binding to the Y1 receptor, the incorporation of an additional amino alkyl functionality to the structure of 33 was explored. Methyl substi tution was used to probe where substitution on the aromatic ring was b est tolerated. In this fashion, the C-4 was chosen for the substitutio n of the second aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Functionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the dibasic benzimidazoles 55-62. Among them, BI 56 demonstrated a K-i of 0.0017 mu M, which was 400-fold more potent than 33. To evaluate i f there was a stereoselective effect on affinity for these BIs, the fo ur constituent stereoisomers (69-72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs w as confirmed by measuring the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP. The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was also shown.