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Aleglitazar: A Case Study

Quite some time ago, the ligand-dependent transcription factors Peroxisome Proliferator Activated Receptor-alpha and -gamma (PPARgamma) were identified as primary molecular targets for the antidiabetic thiazolidinediones (gamma) and the lipid lowering fibrates (alpha), respectively. The profile of a dual PPARalpha/gamma agonist appeared well-suited for addressing both hyperglycemia and dyslipidemia in one drug and lowering the enhanced cardiovascular risk of diabetic patients. Capitalizing on X-ray structural data obtained with known reference compounds as well as relying on detailed molecular modelling studies in combination with chemical intuition, novel PPAR ligands have been designed and synthesised. A new, highly promising class of dual agonists, alpha-alkoxy-benzothiophenyl-propionic acids, has been discovered. In depth evaluation of this compound class led to the identification of Aleglitazar. It interacts as balanced coagonist with similar low nanomolar IC50 and EC50 values with human PPAR with similar low nanomolar IC50 and EC50 values with human PPARuman PPAREC at the PPARdelta receptor. In several murine diabetic models, Aleglitazar by far exceeded the glucose lowering and insulin sensitizing effects seen with Rosiglitazone or Pioglitazone. The balanced in vitro and in vivo profile of Aleglitazar, together with the excellent drug-likeness of the compound, exciting data from a Rhesus monkey study, and the absence of off-target effects rendered this molecule an ideal candidate for clinical development. Phase II clinical trials with Aleglitazar have been successfully completed in 2008. In February 2010, it entered into Phase III studies.

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09 Dec 2014
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