title: Lead optimization strategies and tactics applied to the discovery of melanin concentrating hormone receptor 1 antagonists.
abstract: The discovery of small molecule melanin concentrating hormone receptor (MCHr1) antagonists as novel therapeutic agents for the treatment of obesity has been actively pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 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 MCHr1 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 MCHr1 antagonist for the treatment of obesity, we were unable to deliver a candidate compound that attained an acceptable therapeutic index (TI = 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 MCHR1 receptor antagonists suffer from receptor cross-reactivity that leads to cardiovascular toxicity at low multiples of their therapeutic plasma concentration.
authors: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. phil.kym@abbott.com
authors: Philip R
authors: PR
authors: Kym
authors: Andrew S
authors: AS
authors: Judd
authors: John K
authors: JK
authors: Lynch
authors: Rajesh
authors: R
authors: Iyengar
authors: Anil
authors: A
authors: Vasudevan
authors: Andrew J
authors: AJ
authors: Souers
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor