Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) withthe bicyclo[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 (∼4-fold ↑ C_max and AUC values relative to 1) in a mouse model of γ-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., γ-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.

中文翻译：

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双环[1.1.1]戊烷基作为非经典的苯基环生物甾醇在有效和口服活性γ-分泌酶抑制剂设计中的应用

用双环[1.1.1]戊烷基元取代γ-分泌酶抑制剂1（BMS-708,163）中对位中央的氟苯基环导致化合物3的发现，该化合物3是一种等价的酶抑制剂，在被动渗透性和水溶性。改良后的3的生物制药特性转化为出色的口服吸收特性（相对于1的〜4倍↑ C _max和AUC值）在γ-分泌酶抑制的小鼠模型中。此外，针对其他氟苯基取代基的SAR研究表明，在实现性能（例如，γ-分泌酶抑制，水溶性/通透性，体外代谢稳定性）。总的来说，这项工作扩大了[1.1.1]自行车的应用范围，超出了单纯的“间隔”单元的应用范围，并且为芳香族环数影响理化参数和总体上像毒品。