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.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/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 , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Six crystalline components were isolated from the lipophilic fraction of Artemisia annua L. They have been identified as four sesquiterpenes, one flavonol and one coumarin. Qinghaosu I and III are new sesquiterpenes. Five main constituents, camphene, iso-artemisia ketone, 1-camphor, β-carophyllene, and β-pinene were identified from the volatile oil of this herb.
