540510-97-2Relevant articles and documents
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
Johansson, Anders,L?fberg, Christian,Antonsson, Madeleine,Von Unge, Sverker,Hayes, Martin A.,Judkins, Robert,Ploj, Karolina,Benthem, Lambertus,Lindén, Daniel,Brodin, Peter,Wennerberg, Marie,Fredenwall, Marléne,Li, Lanna,Persson, Joachim,Bergman, Rolf,Pettersen, Anna,Gennemark, Peter,Hogner, Anders
supporting information, p. 2497 - 2511 (2016/04/10)
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.
