Author: Shah, Devang Praful ; Washburn, William N ; Mahammad, Shahe ; Robl, Jeffrey A ; Patankar, Vidya ; Mandal, Umasankar ; A M Subbaiah, Murugaiah ; Murphy, Brian J ; Rami, Bhadresh ; Huang, Christine ; Nutakki, Ravikumar ; Bhaskaran, Selvakumar

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.

01 Dec 2021·Nature Reviews EndocrinologyQ1 · MEDICINE

Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis

Q1 · MEDICINE

Review

Author: Schwaninger, Markus ; Schneeberger, Marc ; Al-Massadi, Omar ; López, Miguel ; Dieguez, Carlos ; Nogueiras, Ruben ; Prevot, Vincent

Melanin-concentrating hormone (MCH) is a small cyclic peptide expressed in all mammals, mainly in the hypothalamus. MCH acts as a robust integrator of several physiological functions and has crucial roles in the regulation of sleep-wake rhythms, feeding behaviour and metabolism. MCH signalling has a very broad endocrine context and is involved in physiological functions and emotional states associated with metabolism, such as reproduction, anxiety, depression, sleep and circadian rhythms. MCH mediates its functions through two receptors (MCHR1 and MCHR2), of which only MCHR1 is common to all mammals. Owing to the wide variety of MCH downstream signalling pathways, MCHR1 agonists and antagonists have great potential as tools for the directed management of energy balance disorders and associated metabolic complications, and translational strategies using these compounds hold promise for the development of novel treatments for obesity. This Review provides an overview of the numerous roles of MCH in energy and glucose homeostasis, as well as in regulation of the mesolimbic dopaminergic circuits that encode the hedonic component of food intake.

01 Feb 2015·Expert Opinion on Therapeutic PatentsQ2 · MEDICINE

Novel MCH₁receptor antagonists: a patent review

Q2 · MEDICINE

Review

Author: Johansson, Anders ; Loefberg, Christian

INTRODUCTIONThe cyclic neuropeptide melanin-concentrating hormone (MCH) shows appetite-stimulating effects indicating an involvement in obesity. Large efforts have been invested in discovery programs to identify novel MCH1 receptor (MCHR1) antagonists. Other indications where MCHR1 antagonists may have a potential use include: anxiety/depression and, more recently, inflammatory responses in the gastrointestinal tract.AREAS COVEREDThe current review covers the patent literature on MCHR1 antagonists published from November 2010 to March 2014. The applications have been grouped by filing company, and weight has been put on commenting compounds with disclosed in vivo biological data.EXPERT OPINIONAchieving sufficient separation of the human EtheR-a-Go-go channel has prevented many programs from reaching the clinic. For clinical programs, CNS exposure seems to have been a major challenge. Although clinical studies of MCHR1 antagonists have not been able to conclusively evaluate the concept, the body of evidence suggesting a role for MCHR1 antagonists in weight management is strong and novel chemical series still appear in the patent literature. An MCHR1 antagonist with the appropriate physical chemical properties is needed to convincingly evaluate the MCHR1 concept for obesity treatment and, as knowledge from previous programs are shared, the discovery of such a compound should be achievable.

100 Deals associated with MCHR1 inhibitors(Schering-Plough Research Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	US	Schering-Plough Research Institute	28 Jul 2005

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