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 physicochemi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-03, Vol.59 (6), p.2497-2511
Main Authors: Johansson, Anders, Löfberg, 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
Format: Article
Language:English
Subjects:
Animals
Anti-Obesity Agents - pharmacology
Azetidines - chemical synthesis
Azetidines - pharmacology
Body Weight - drug effects
Brain - drug effects
Brain - metabolism
Drug Discovery
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Female
Lipids - chemistry
Mice
Mice, Inbred C57BL
Models, Molecular
Oxadiazoles - chemical synthesis
Oxadiazoles - pharmacology
Potassium Channel Blockers - chemical synthesis
Potassium Channel Blockers - pharmacology
Receptors, Somatostatin - antagonists & inhibitors
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01654