Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties

A novel
series of melanin concentrating hormone receptor 1 (MCHr1)
antagonists were the starting point for a drug discovery program that
culminated in the discovery of 103 (AZD1979). The lead
optimization program was conducted with a focus on reducing lipophilicity
and understanding the physicochemical properties governing CNS exposure
and undesired off-target pharmacology such as hERG interactions. An
integrated approach was taken where the key assay was ex vivo receptor
occupancy in mice. The candidate compound 103 displayed
appropriate lipophilicity for a CNS indication and showed excellent
permeability with no efflux. Preclinical GLP toxicology and safety
pharmacology studies were without major findings and 103 was taken into clinical trials.