ABSTRACT
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Subject(s)
Piperazines/chemistry , Receptor, Melanocortin, Type 4/agonists , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Eating/drug effects , Haplorhini , Mice , Obesity/drug therapy , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/therapeutic useABSTRACT
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
Subject(s)
Aza Compounds/pharmacology , Eating/drug effects , Penile Erection/drug effects , Piperazines/pharmacology , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Aza Compounds/chemical synthesis , Humans , Male , Microsomes, Liver/metabolism , Piperazines/chemistry , Piperidines/chemical synthesis , Protein Binding , Quinuclidines/chemistry , Rats , Rats, Sprague-Dawley , Rodentia , Structure-Activity Relationship , Time FactorsABSTRACT
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. The 5- and 6-alkylated piperazine compounds exhibit low bioactivation potential as measured by covalent binding in microsome preparations.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Humans , Piperazines/metabolism , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.