Discovery of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an Active Metabolite. A Novel, Potent and Selective Cannabinoid-1 Receptor Inverse Agonist with High Antiobesity Efficacy in DIO Mice

Abstract

By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

“…Therefore, it appears that the amide group should be replaced by a moiety capable of acting as a hydrogen-bond acceptor so not to completely lose this binding interaction. A number of relevant derivatives with bioisosteric substitutes of the amide group by sulphonamide (Srivastava et al , 2008), oxadiazole (Lee et al , 2008) and imidazol-4-thione (Wu et al , 2009) have been attempted; however, these derivatives either lost binding affinity for CB 1 or retained inverse agonism. In terms of size and spatial requirements, a ketone is an excellent replacement for an amide, but any functional consequences of a small, partially negative charge residing on the oxygen of the ketone are difficult to foresee.…”

Perspectives of CB1 Antagonist in Treatment of Obesity: Experience of RIO-Asia

“…Perceptively, to avoid untoward CNS side effects in drug discovery for the intervention of the endocannabinoids system, an appealing strategy of development of peripherally restricted and highly CB1/CB2 selective antagonists may be desired. Some compounds of this kind have been shown to have promising results in lowering propensity to pass the blood-brain barrier with preserved weight-reducing effects in DIO mice [36, 37]. Another peripheral-acting CB1 neutral antagonist has been shown to have weight-independent effects on improving cardiometabolic risks and fatty liver in mouse models of obesity [38].…”

Synthesis of Novel Pyrazole Derivatives Bearing 1,2,4-Triazole Moiety as Potential Anticancer Agents

“…The synthetic route of the designated compounds was shown in scheme 1. 5-(4chlorophenyl)-1-(2,4-dichlorophenyl)-4methyl-1H-pyrazole-3-carboxylate 3 was synthesised through treatment of 1-(4chlorophenyl)propanone 1 with diethyl oxalate in the presence of LHMDS as a base to afford lithium salt 2 in 80% yield, which in turn was coupled with 2,4-dichlorophenylhydrazine hydrochloride in ethanol followed by intramolecular cyclization in acetic acid under refluxing conditions to provide the pyrazole-3carboxylic acid ethyl ester 3 in 55% yield over two steps 50 . The 1 H-NMR spectrum of 3 showed a singlet equivalent to three protons at δ 2.31 ppm which assigned to methyl groupand a quartet at 4.42 ppm and a triplet at 1.39 ppm related to ethoxy moiety as well as aromatic protons appeared at expected chemical shift.…”