ABSTRACT
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Subject(s)
Naphthyridines/chemistry , Pyridines/chemistry , Receptor, Cannabinoid, CB1/agonists , Weight Loss/drug effects , Administration, Oral , Animals , Eating , Humans , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Receptor, Cannabinoid, CB1/drug effects , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/drug effects , Structure-Activity RelationshipABSTRACT
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Subject(s)
Drug Design , Furans/chemical synthesis , Pyridines/chemical synthesis , Receptor, Cannabinoid, CB1/agonists , Animals , Benzopyrans , Dogs , Furans/chemistry , Furans/pharmacology , Haplorhini , Humans , Inhibitory Concentration 50 , Mice , Mice, Knockout , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Cannabinoid, CB1/genetics , Structure-Activity RelationshipABSTRACT
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyridines/chemistry , Pyridines/chemical synthesis , Receptor, Cannabinoid, CB1/agonists , Animals , Behavior, Animal/drug effects , Drug Design , Feeding Behavior/drug effects , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Temperature , Toluene/chemistryABSTRACT
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.
