ABSTRACT
Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
Subject(s)
Ether-A-Go-Go Potassium Channels/metabolism , Melanins/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Urea/pharmacology , Chemistry, Pharmaceutical , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Protein Binding , Urea/chemistryABSTRACT
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Phenylurea Compounds/chemical synthesis , Piperazines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Administration, Oral , Animals , Anti-Obesity Agents/pharmacology , Biological Availability , Body Weight/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Eating/drug effects , Half-Life , Male , Obesity/drug therapy , Phenylurea Compounds/pharmacology , Piperazines/pharmacology , Radioligand Assay , Rats , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Tissue Distribution , Urea/pharmacologyABSTRACT
Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.
Subject(s)
Aminobiphenyl Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Heptanes/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Cell Line , Cricetinae , Drug Evaluation, Preclinical , Heptanes/pharmacology , Mice , Molecular Structure , Mutagens/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models.
