Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonists for the Treatment of Obesity

다국어 초록 (Multilingual Abstract)

Obesity is gradually becoming a leading cause of morbidity as a result of an increase in associated risk factors such as dyslipidemia, type 2 diabetes, stroke, cardiovascular disease, and cancer. There are only two drugs currently approved in the United States for chronic treatment of obesity, Roche's Xenical(Orlistat), which blocks fat absorption from the gut, and Abbott's Meridia(Sibutramine), which is a mixed 5HT-NE uptake inhibitor. Recent pharmacological approaches to induce weight loss have included modulation of several metabolic process. One of the most promising new pharmacological targets in these endeavors is the melanin-concentrating hormone(MCH).
MCH is a cyclic 19-amino acid peptide that is produced predominantly in neurons in the lateral hypothalamus and zona incerta. Several lines of evidence have shown that MCH-peptide plays a major role in body weight regulation in rodents: 1) Intracerebroventricular(icv) administration of MCH in rats stimulates food intake; 2) Chronic administration of the MCH peptide leads to increased body weight; and 3) Transgenic mice overexpressing the MCH gene are susceptible to insulin resistance and obesity; 4) Mice lacking the gene encoding MCH are hypophagic, lean, and maintain elevated metabolic rates; 5) MCHR1 null mice are lean, have decreased leptin and insulin levels, and are resistant to diet-induced obesity despite exhibiting a hypermetabolic phenotype.
Small molecule antagonists of MCHR1 have been heavily pursued by many laboratories trying to find an effective anti-obesity agent. By November 2004, two MCHR1 antagonists(AMG-076, Amgen; GSK-856464, GlaxoSmithKline) had already entered Phase I clinical trials. However, no changes in status have been reported for either MCHR1 program to date.
Several potent MCHR1 antagonists based on benzimidazole scaffolds have been designed, synthesized, and evaluated for the treatment of obesity. SAR analysis showed that some compounds were potent antagonists, with activities below 10 nM, which demonstrate very good oral bioavailability and other pharmacokinetic parameters in rats. Oral administration of the most potent compound in this class in the animal modelled to significant reduction of weight.