ABSTRACT
Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.
Subject(s)
Drug Discovery , Indazoles/chemical synthesis , Microsomes, Liver/drug effects , Triazoles/chemical synthesis , Dose-Response Relationship, Drug , Humans , Indazoles/chemistry , Indazoles/therapeutic use , Molecular Structure , Muscular Dystrophy, Duchenne/drug therapy , Solubility , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.