title: Melanin concentrating hormone receptor 1 (MCHR1) antagonists-Still a viable approach for obesity treatment?
abstract: Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.
authors.affiliation: LEO Pharma, Chemical Research, Industriparken 55, DK-2750 Ballerup, Denmark. thomas.hogberg@leo-pharma.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Sasmal
mesh_terms: D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; D051638:Ether-A-Go-Go Potassium Channels; C103263:MCHR1 protein, human; D009281:Naphthalenes; D010880:Piperidines; D011743:Pyrimidines; D017481:Receptors, Somatostatin; C464854:SNAP7941; C457679:T-226296