Lead optimization strategies and tactics applied to the discovery of melanin concentrating hormone receptor 1 antagonists

The discovery of small molecule melanin concentrating hormone receptor (MCHrl) antagonists as novel therapeutic agents for the treatment of obesity has been actively pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHrl antagonists have been identified and shown to deliver weight loss in animal models of obesity, many of these lead compounds have been found to cross-react with the hERG channel and/or demonstrate deleterious effects on cardiovascular hemodynamic parameters. This review describes an approach to rapidly identifying safer MCHrl antagonists by placing assays to assess cardiovascular safety early in the lead optimization compound prioritization process. Ultimately, despite putting significant effort toward the discovery of a MCHrl antagonist for the treatment of obesity, we were unable to deliver a candidate compound that attained an acceptable therapeutic index (Tl = 30-100) in our in vivo models. Our inability to identify a compound with an acceptable therapeutic index was driven by two primary factors: 1) high levels of sustained drug exposure in the brain was required to achieve efficacy and 2) many small molecule MCHRl receptor antagonists suffer from receptor cross-reactivity that leads to cardiovascular toxicity at low multiples of their therapeutic plasma concentration.