Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

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Mihalic JT, Fan P, Chen X, Chen X, Fu Y, Motani A, Liang L, Lindstrom M, Tang L, Chen JL, Jaen J, Dai K, Li L

Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3781-5. doi: 10.1016/j.bmcl.2012.04.006. Epub 2012 Apr 7.

PubMed ID

22542010 [ View in PubMed

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Abstract

An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Terfenadine	Potassium voltage-gated channel subfamily H member 2	IC 50 (nM)	56	N/A	N/A	Details