title: 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.
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.
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johansson
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Löfberg
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Antonsson
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Sverker
authors.initials: S
authors.lastname: von Unge
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Hayes
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Judkins
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ploj
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Benthem
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindén
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Brodin
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Wennerberg
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Marléne
authors.initials: M
authors.lastname: Fredenwall
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Lanna
authors.initials: L
authors.lastname: Li
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Persson
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bergman
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Pettersen
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Gennemark
authors.affiliation: Cardiovascular & Metabolic Diseases iMed and ‡Global Medicines Development, AstraZeneca Gothenburg , 431 83 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hogner
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C000609913:AZD1979; D019440:Anti-Obesity Agents; D001384:Azetidines; D051638:Ether-A-Go-Go Potassium Channels; D008055:Lipids; C491209:Mchr1 protein, mouse; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D017481:Receptors, Somatostatin