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
MB243 (a 1,3-disubstituted piperazine) is a new, potent, and selective melanocortin receptor subtype-4 agonist with potential application in the treatment of obesity and/or erectile dysfunction. MB243 was observed to covalently bind extensively to liver microsomal proteins from rats and humans. In the presence of glutathione, two thioether adducts were detected in liver microsomal incubations by radiochromatography and LC/MS/MS analysis. These adducts were also formed when bile duct-cannulated rats were dosed with MB243. The two adducts were isolated, and their structures were determined by accurate mass MS/MS and NMR analyses. The proposed structures resulted from a novel contraction of the piperazine ring to yield a substituted imidazoline. A mechanism is proposed, which involves an initial six electron oxidation of the piperazine ring to form a reactive intermediate, which is trapped by glutathione. Hydrolysis of the glutamic acid residue followed by internal aminolysis by the cysteine amino group resulted in opening of the piperazine ring, which is followed by ring closure to an imidazoline. The resulting cysteinyl-glycine conjugate underwent subsequent hydrolysis of the glycine residue. Understanding of the mechanism of bioactivation led to the design of MB243 analogues that exhibited reduced covalent protein binding.
Subject(s)
Imidazolines/chemical synthesis , Imidazolines/metabolism , Piperazines/pharmacokinetics , Animals , Bile/drug effects , Biotransformation , Cyclization , Glutathione/drug effects , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , NADP/drug effects , Piperazines/administration & dosage , Piperazines/chemical synthesis , Protein Binding , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Piperazines/pharmacology , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Dogs , Erectile Dysfunction/drug therapy , Haplorhini , Male , Mice , Obesity/drug therapy , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/therapeutic use , RatsABSTRACT
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.
