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
  • 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.