Synthesis and Evaluation of a Series of Novel 2-[(4-Chlorophenoxy)methyl]- benzimidazoles as Selective Neuropeptide Y Y1 Receptor Antagonists

Abstract

A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept constant and 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 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of 33 was explored. Methyl substitution was used to probe where substitution on the aromatic ring was best tolerated. In this fashion, the C-4 was chosen for the substitution 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 Ki of 0.0017 microM, which was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity for these BIs, the four constituent stereoisomers (69-72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs was 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.

Indion 190 resin: efficient, environmentally friendly, and reusable catalyst for synthesis of benzimidazoles, benzoxazoles, and benzothiazoles

“…They have also been used as ligands for asymmetric transformations (7). Benzimidazole derivatives are a unique and broad-spectrum class of antirhino/ enteroviral agents such as antiulcerative (8) and antiallergic (9), are effective against the human cytomegalovirus (10), and are also efficient selective neuropeptide Y Y1 receptor antagonists (11).…”

Synthesis and Molecular Docking for Antiinflammatory Studies of 2-(Arylmethyl)-1-ethyl-1H-benzo[d]imidazol-5-amines

“…IR spectra were recorded by Perkin-Elmer 1000 instrument in KBr pellets. 1 H NMR spectra were recorded in CDCl3 or DMSO-d6 solvent using tetramethylsilane as internal standard by 400 MHz spectrometer. By Jeol-JMS D-300 spectrometer, mass spectra were recorded.…”

“…They prove selective neuropeptides YY1 receptor antagonists [1], antitumor agents [2], potent inhibitors of TIE-2 and VEGFER-2 tyrosine kinase receptors [3] and 5-HT3 antagonists [4]. Other benzimidazole compounds initiate commercial use in veterinarian medication as anthelmintic agents and in various human therapeutic areas such as handling of antihistaminic and ulcers [5].…”

Crystal and Molecular Structure of 2-(2-Fluoro-phenyl)-1H-benzoimidazole

“…Benzoimidazoles and their derivatives exhibit a number of important pharmacological properties, such as antihistaminic 6 , anti-ulcerative 7 , antiallergic 8 and antipyretic 9 . In addition, benzoimidazole derivatives are effective against the human cytomegalovirus (HCMV) 10 and are also efficient selective neuropeptide Y Y1 receptor antagonists 11 . Most of the described methods for the synthesis of benzoimidazoles make use of volatile organic solvents and involve solid-phase synthesis via o-nitroanilines 12 -15 or the condensation of o-phenylenediamines with carboxylic acid derivatives 16 , aldehydes 17 -22 and aryl halides 23 .…”