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Ketoconazole enantiomer for the treatment of diabetes mellitus.

Expert opinion on investigational drugs (2010-01-06)
Richard Arakaki, Bernice Welles
ABSTRACT

The impact of hypercortisolism on multiple metabolic conditions is well recognized; the metabolic manifestations of Cushing's syndrome overlap with those seen in type 2 diabetes and the metabolic syndrome. Ketoconazole (KTZ), a widely used antifungal agent that inhibits various enzymes in adrenal cortisol synthesis, is effective in treating hypercortisolemia, but its use is limited by toxicities. KTZ is a racemic compound of two cis-enantiomers: (2R,4S)-(+)-KTZ and (2S,4R)-(-)-KTZ. The consideration of an enantiomer with selective effect but minimal metabolic toxicity has driven the development of DIO-902 ([2S,4R]-[-]-KTZ) for the treatment of patients with type 2 diabetes and the metabolic syndrome. To evaluate the safety profile and effect of KTZ enantiomer, (2S,4R)-(-)-KTZ, on cortisol production, glycemia, and lipid profiles in patients with type 2 diabetes. Review of multiple published studies and examination of preliminary results from a Phase IIb clinical trial. Twelve weeks of treatment with DIO-902 resulted in reduced levels of HbA1c, FPG, total and LDL cholesterol as well as weight loss and decreased BP. In a previously conducted Phase IIa study, C-reactive protein levels decreased with DIO-902 treatment. Unfortunately, the development of this agent has been terminated due to unacceptable safety profiles.

MATERIALS
Product Number
Brand
Product Description

USP
Ketoconazole, United States Pharmacopeia (USP) Reference Standard
Supelco
Ketoconazole, Pharmaceutical Secondary Standard; Certified Reference Material
Ketoconazole, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Ketoconazole, 99.0-101.0% (EP, titration)
Sigma-Aldrich
Ketoconazole