2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Mar 24;59(6):2497-511. doi: 10.1021/acs.jmedchem.5b01654.
Anders Johansson 1,  Christian Löfberg 1,  Madeleine Antonsson 1,  Sverker von Unge 1,  Martin A Hayes 1,  Robert Judkins 1,  Karolina Ploj 1,  Lambertus Benthem 1,  Daniel Lindén 1,  Peter Brodin 1,  Marie Wennerberg 1,  Marléne Fredenwall 1,  Lanna Li 1,  Joachim Persson 1,  Rolf Bergman 1,  Anna Pettersen 1,  Peter Gennemark 1,  Anders Hogner 1
Affiliations

Affiliation

  • 1 Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
PMID: 26741166 DOI: 10.1021/acs.jmedchem.5b01654
Abstract

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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