Synthesis and structure-activity relationship of novel diarylpyrazole imide analogues as CB1 cannabinoid receptor ligands.
A myriad of research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, was discovered for an obesity treatment. In this research, extended series, based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. In the present study, N-piperidinylcarboxamide group of rimonabant was replaced with the corresponding sulfonamide, imide, N-methyl imide and methylenediamide, respectively. The SAR studies to optimize the CB1 binding affinity led to the potent imide derivatives. The in vivo efficacy test of a derivative (16f) gave a promising result for this novel scaffold. In order to explore physicochemical properties (hydrophobic, steric and electronic) of the representative imide derivatives responsible for their CB1 receptor binding affinity, quantitative structure activity relationship (QSAR) studies were performed. Hansch QSAR models, which were moderate in the explanation for SAR, were generated with hydrophobic, steric and electronic properties of substituents. Especially, the Taft Es-based parabolic model was obtained with the best correlation result (r(2)=0.846).
Song
Kwang-Seop
KS
Central Research Laboratories, Green Cross Corporation, Yongin, 446-770, Republic of Korea.
Kim
Min Ju
MJ
Seo
Hee Jeong
HJ
Lee
Sung-Han
SH
Jung
Myung Eun
ME
Kim
Soo-Un
SU
Kim
Jeongmin
J
Lee
Jinhwa
J