jm300094u_si_001.pdf (253.17 kB)
Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γ-Secretase Inhibitor
journal contribution
posted on 2012-04-12, 00:00 authored by Antonia F. Stepan, Chakrapani Subramanyam, Ivan V. Efremov, Jason
K. Dutra, Theresa J. O’Sullivan, 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’DonnellReplacement of the central, para-substituted
fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with
the 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 ↑ Cmax 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.