Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active 纬-Secretase Inhibitor

详细信息    查看全文

• 作者：Antonia F. Stepan ; Chakrapani Subramanyam ; Ivan V. Efremov ; Jason K. Dutra ; Theresa J. O鈥橲ullivan ; Kenneth J. DiRico ; W. Scott McDonald ; Annie Won ; Peter H. Dorff ; Charles E. Nolan ; Stacey L. Becker ; Leslie R. Pustilnik ; David R. Riddell ; Gregory W. Kauffman ; Bethany L. Kormos ; Liming Zhang ; Yasong Lu ; Steven H. Capetta ; Michael E. Green ; Kapil Karki ; Evelyn Sibley ; Kevin P. Atchison ; Andrew J. Hallgren ; Christine E. Oborski ; Ashley E. Robshaw ; Blossom Sneed ; Christopher J. O鈥橠onnell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3414-3424
• 全文大小：471K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

Replacement of the central, para-substituted fluorophenyl ring in the 纬-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 鈫?C_max and AUC values relative to 1) in a mouse model of 纬-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., 纬-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 鈥渟pacer鈥?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.