Melanin-Concentrating Hormone Receptor 1 Antagonists for Treatment of Obesity

Ahmed F Abdel-Magid

doi:10.1021/acsmedchemlett.5b00077

editorial

. 2015 Feb 26;6(4):367–368. doi: 10.1021/acsmedchemlett.5b00077

Melanin-Concentrating Hormone Receptor 1 Antagonists for Treatment of Obesity

Ahmed F Abdel-Magid ^1,^*

PMCID: PMC4416430 PMID: 25941549

Title:	Heterocyclic Compound
Patent Application Number:	WO 2015/005489 Al	Publication date:	15 January 2015
Priority Application:	JP 2013–143940	Priority date:	9 July 2013
Inventors:	Igawa, H.; Takahashi, M.; Kakegawa, K.; Ikoma, M.; Aida, J.
Assignee Company:	Takeda Pharmaceutical Company Limited; 1–1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045, Japan
Disease Area:	Obesity	Biological Target:	Melanin-concentrating hormone receptor 1 (MCHR1)
Summary:	The invention in this patent application relates to 2H-indazole derivatives represented generally by formula (I). These compounds possess melanin-concentrating hormone receptor antagonistic activities and may be useful for the treatment or prophylaxis of obesity.
	The melanin-concentrating hormone (MCH) is a cyclic 19-amino acid hypothalamus-derived peptide that shows appetite stimulant activity. Studies have indicated that antagonism of the melanin-concentrating hormone receptor 1 (MCHR1) is a promising therapeutic target for the treatment of obesity. MCH knockout mice behave normally; however, they show significantly decreased food intake and lighter body weights compared to normal mice. In addition, MCHR1-deficient mice have been reported to show lean phenotypes.
	Therefore, the MCHR1 antagonists such as the compounds described in this patent application may provide a promising treatment for obesity by virtue of their properties as excellent appetite suppressants.
Important Compound Classes:
Key Structures:	The inventors reported the structures of 48 examples of formula (I) including the following four representative examples:
Biological Assay:	• Determination of human MCH receptor 1 (MCHR1) competitive inhibitory activity using binding assay • Measurement of MCH receptor 1 antagonistic activity using Ca²⁺ mobilization assay • Evaluation of anorectic effect using male diet-induced obese F344/Jcl rats • hERG activity measurement by IonWorks Quattro
Biological Data:	The biological data obtained from testing the representative examples (structures shown above) are listed in the following table:
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