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).
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Melanin-concentrating hormone promotes feeding through the lateral septum.
Prog Neuropsychopharmacol Biol Psychiatry
October 2024
Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address:
Feeding is necessary for survival but can be hindered by anxiety or fear, thus neural systems that can regulate anxiety states are key to elucidating the expression of food-related behaviors. Melanin-concentrating hormone (MCH) is a neuropeptide produced in the lateral hypothalamus and zona incerta that promotes feeding and anxiogenesis. The orexigenic actions of MCH that prolong ongoing homeostatic or hedonic feeding are context-dependent and more prominent in male than female rodents, but it is not clear where MCH acts to initiate feeding.
View Article and Find Full Text PDFIncentive motivation for palatable food blocked by intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonist in female rats.
Pharmacol Biochem Behav
December 2024
Department of Psychological Sciences, University of Missouri, Columbia, MO, USA.
Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food.
View Article and Find Full Text PDFExploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy.
Eur J Med Chem
October 2024
Department of Metabolic Diseases Chemistry, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, NJ, 08543-4000, USA.
With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.
View Article and Find Full Text PDFChronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.
Int J Neuropsychopharmacol
January 2024
Department of Pharmacology, Peking University, School of Basic Medical Science, Beijing, China.
Article Synopsis
- Melanin-concentrating hormone (MCH) in the locus coeruleus (LC) may play a significant role in depression by affecting norepinephrine levels.
- Chronic unpredictable stress (CUS) led to increased MCH levels and decreased MCHR1, which correlated with depression-like behaviors in rats, while blocking MCHR1 showed antidepressant effects.
- The study highlights the potential of the MCH/MCHR1 system in the LC as a target for understanding and potentially treating depression-related mechanisms.
Computational prediction of analog compounds of the membrane protein MCHR1 antagonists ALB-127158 and KRX-104130.
J Bioenerg Biomembr
December 2023
Faculty of Health Sciences, Department of Nutrition and Dietetics, Artvin Coruh University, Artvin, Turkey.
Obesity, which is already pervasive throughout the world, endangers public health by raising the prevalence of metabolic disorders and making their treatment more difficult. The development of drugs to treat obesity is a focus of effort. Melanin concentrated hormone receptor 1 (MCHR1) is the target of some of these therapeutic possibilities since as increased levels of melanin concentrated hormone have been found in obesity models.
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