Replacement of the para-substituted fluorophenyl ring in the ?-secretase inhibitor BMS-708,163 with the bicyclo[1.1.1]pentane motif led to the discovery of an equipotent enzyme inhibitor with significant improvements in passive permeability, metabolic stability and aqueous solubility. These favorable in vitro properties translated into a significantly improved oral absorption and can be attributed to the increased 3-dimensionality relative to the parent biaryl compound. This work enhances the scope of the [1.1.1]-bicycle beyond that of a mere spacer unit and presents a case for its broader application as a phenyl group replacement in scenarios in which the aromatic ring count negatively impacts biopharmaceutical properties and overall drug-likeness.The presentation outlines the rational design that led to this finding and demonstrates how the unusual [1.1.1]-moiety enabled fast project advancement and access to novel IP and design space. A matched molecular pair analysis of Pfizer's compound collection will be included to understand whether the observed changes in in vitro parameters are a general phenomenon or limited to this specific series of ?-secretase inhibitors.

Use of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl bioisostere with increased 3-dimensionality

247th National Meeting (2014)

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