
Journal of Medicinal Chemistry p. 2497 - 2511 (2016)
Update date:2022-07-29
Topics:
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
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.
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