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
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.
