51. Overcoming retinoic acid receptor-α based testicular toxicity in the optimisation of glucokinase activators
- Author
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Graeme R. Robb, Kurt Gordon Pike, Darren Mckerrecher, Huw B. Jones, Brendan Leighton, Iain J. Brogan, Craig Johnstone, Michael J. Waring, and Matthew P. Coghlan
- Subjects
Pharmacology ,chemistry.chemical_classification ,Glucokinase ,Organic Chemistry ,Retinoic acid ,Pharmaceutical Science ,Biology ,Biochemistry ,Small molecule ,Retinoic acid receptor ,Oral agents ,chemistry.chemical_compound ,Enzyme ,chemistry ,Drug Discovery ,Molecular Medicine ,Testicular toxicity ,Pharmaceutical sciences - Abstract
Small molecule activators of the glucokinase enzyme have the potential to deliver a level of glycaemic control that is superior to current oral agents and hence have great promise as new therapies for Type 2 Diabetes. As such, attempts to discover glucokinase activators suitable for clinical development have been the focus of many major pharmaceutical research programmes. Here we describe how we have overcome a testicular toxicological liability in our pyridine acid lead series, which we show can be ascribed to antagonism of the retinoic acid receptor-α.
- Published
- 2011