Editorial [Hot Topic:Melanin-Concentrating Hormone (MCH) (Guest Editor: Andrew J. Souers)]

Melanin-concentrating hormone (MCH) is a neuropeptide that plays a role in multiple physiological processes, including the regulation of feeding behavior and energy balance. Since the discovery of the first MCH receptor in 1999, referred to as MCHr1, reports of mice deficient in both the MCH peptide as well as the receptor have been disclosed. Genetically altered mice lacking the gene encoding MCH are hypophagic, lean, and maintain elevated metabolic rates while those lacking the gene encoding MCHr1 maintain elevated metabolic rates yet remain lean despite hyperphagia on a normal diet. While some differences are apparent in the two phenotypes, the possible result of other functional peptides being derived from the prepro MCH gene, both results support a role for MCHr1 antagonism in the treatment of obesity. This and other data have since fueled an aggressive effort by the pharmaceutical industry to identify small molecule antagonists that are suitable for the mentioned indication. Since the first disclosure of Takeda's T-226296, which appeared in print in 2002, a large number of diverse small molecule antagonists has been reported. Many of these have demonstrated dose dependent weight loss and/or food intake in various animal models. Interestingly, some reported compounds cause weight loss while not affecting food intake, which raises questions regarding the role of increased energy expenditure. Finally, MCHr1 has been implicated in behavioral roles, and significant effort has been expended in deriving utility from MCHr1 antagonists as anti-depressants and anxiolytics as well. This collection of accounts will focus on the original indication for MCHr1 antagonists. Seminal work preceding the development of small molecule antagonists was provided by the identification of receptor selective peptide agonists and antagonists. These peptides were then used to delineate a number of functions that were dependent on receptor activation or antagonism. In the first contribution, Maria Bednarek, of Merck Research Laboratories, provides a synopsis of efforts to identify these peptides. Additionally, a description of the SAR is included, along with the results of several in vitro and in vivo studies. This paved the way for small molecule efforts at the same company, and Robert DeVita describes some of these efforts in the subsequent manuscript. By first identifying novel 2-aminoquinoline hits from a high-throughout screen (HTS), DeVita's group was able to optimize the hit compounds into potent leads that were suitable for mechanism of action studies in rats. A similar hit-to-lead story emerged from the Schering Plough group, which has published a multitude of high quality manuscripts describing their efforts in the MCHr1 field. A portion of their strategy relied on the identification of suitable replacements for a biphenyl aniline, a moiety with known mutagenic properties. As described by Mark McBriar, this led to the identification of a highly potent and novel class of bicyclohexyl ureas. In order to optimize these compounds for brain penetration and, ultimately, in vivo efficacy, the Schering group relied on a medium throughput ex vivo receptor occupancy assay. This method allowed for the identification of compounds that delivered a considerable reduction in food intake when dosed in diet-induced obese mice (DIO), and the authors were able to clearly demonstrate the correlation between ex vivo binding and longer term in vivo effects. In the fourth contribution, Don Hertzog and Dave Whitty from Glaxo Smithkline provide an overview of their efforts to develop a thieno[3,2-d]pyrimidinone class of MCHr1 antagonists. They describe the systematic optimization of an HTS lead, leading to the identification of a compound class with excellent receptor affinity as well as brain penetration in mice. Additionally, members of this class are among the most efficacious of any MCHR1 antagonists reported, with up to 17% weight loss observed upon once daily oral dosing in DIO mice......