This presentration describes the incorporation of a [1.1.1]bicyclopentane moiety within darapladib, a known LpPLA<sub>2</sub> inhibitor, to act as a bioisosteric phenyl replacement. Computational modelling revealed that the internal aromatic of the bi-aryl system within darapladib was the prime candidate for replacement, since binding to the enzyme should not be perturbed. The subsequent synthesis of the bioisosteric analogue is reported here. Admirable yields were achieved throughout the 10 step synthesis with a dichlorocarbene insertion into a [1.1.0]bicyclobutane system being the key transformation.<br/>Potency, physicochemical and X-ray crystallographic data were all obtained to compare the known inhibitor to its bioisosteric counterpart. These data confirm that the [1.1.1]bicyclopentane bioisostere is indeed tolerated with high potency maintained and notable effects on the physicochemical profile observed.

Synthetic approaches to a [1.1.1]bicyclopentane and its incorporation into darapladib as a phenyl bioisostere

251st National Meeting (2016)

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