Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.
نویسندگان
چکیده
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
منابع مشابه
Antiobesity effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice.
Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinit...
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The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MC...
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ورودعنوان ژورنال:
- Journal of medicinal chemistry
دوره 57 18 شماره
صفحات -
تاریخ انتشار 2014