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.
Subject(s)
Diabetes Mellitus/drug therapy , Drug Discovery , Drug Inverse Agonism , Imidazoles/metabolism , Imidazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Thiones/metabolism , Thiones/pharmacology , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/metabolism , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Cell Line , Diabetes Mellitus/chemically induced , Diabetes Mellitus/metabolism , Diet , Eating/drug effects , Humans , Imidazoles/chemistry , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Male , Mice , Mice, Obese , Rats , Receptor, Cannabinoid, CB2/agonists , Substrate Specificity , Thiones/chemistry , Thiones/therapeutic useABSTRACT
Based on the bioisosteric replacement of the pyrazole C3-carboxamide of rimonabant with a 5-alkyl oxadiazole ring, a novel class of oxadiazole derivatives with promising biological activity towards CB1 receptors was discovered. Among them, compounds with an alkyl linker containing a strong electron-withdrawing group (e.g., CF(3)) and a sterically favorable bulky group (e.g., t-butyl) exhibited excellent CB1 antagonism and selectivity, and thus might serve as potential candidates for further development as anti-obesity agents.
Subject(s)
Amides/chemistry , Amides/metabolism , Piperidines/chemistry , Piperidines/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Cell Line , Humans , Isomerism , Molecular Structure , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Rimonabant , Structure-Activity RelationshipABSTRACT
Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.
Subject(s)
Piperidines/chemistry , Pyrazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Thiophenes/pharmacology , Weight Loss/drug effects , Animals , Binding Sites , Hydrophobic and Hydrophilic Interactions , Mice , Mice, Obese , Piperidines/pharmacology , Pyrazoles/pharmacology , Rimonabant , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
An operationally simple and high-yielding procedure has been developed for the conversion of primary amides to the corresponding nitriles, using ethyl dichlorophosphate/DBU as the mild dehydrating agent.
Subject(s)
Amides/chemistry , Nitriles/chemistry , Molecular Structure , Water/chemistryABSTRACT
Bicyclic isoxazolines and isoxazoles are obtained in good yields by proceeding through a convenient one-pot, two-step procedure utilizing 2,4,6-trichloro-1,3,5-triazine (TCT) as a dehydrating agent.
ABSTRACT
beta-Nitrostyrenes 1 react with trialkylboranes under a nitrogen atmosphere to generate high yields of alkenes 2. The mechanism is proposed to be a free-radical reaction via NO(2)/alkyl substitution since the reaction is stimulated by the presence of a trace of oxygen in the nitrogen or tert-butyl peroxide or by photolysis and is retarded or inhibited by the addition of galvinoxyl to the solution.