Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 7, Pages 3414-3424Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm300094u
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Replacement of the central, para-substituted fluorophenyl ring in the gamma-secretase inhibitor 1 (BMS-708,163) with the bic-yclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (similar to 4-fold up arrow C-max and AUC values relative to 1) in a mouse model of gamma-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., gamma-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere spacer unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
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