Estrogen-related receptor a (ERRa) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis, and the effects of selective modulation of this receptor in vivo have been described in diet-induced models of obesity as well as in overtly diabetic rat models.  We have identified and optimized a series of indazole-based thiazolidenediones, which function in vitro as selective ligands for this receptor.  In the monogenic ob/ob mouse model of obesity, hyperlipidemia, insulin resistance and type 2 diabetes, chronic administration of an ERRa modulator resulted in improvements in glucose tolerance and evidenced dose-dependent reductions in %HbA1c.  In the fa/fa rat, which serves as a monogenic model of prediabetes, chronic administration of the ERRa modulator improved glucose tolerance and favorably impacted other metabolic parameters such as fed insulin, fed glucose, triglycerides and free fatty acids.  A summary of SAR, ADME properties, and efficacy data from this series will be presented.

Indazole-based ligands for estrogen-related receptor α as potential antidiabetic agents

244th National Meeting (2012)

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