2. Academic Validation
  3. 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

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

  • J Med Chem. 2012 Apr 12;55(7):3414-24. doi: 10.1021/jm300094u.
Antonia F Stepan 1,  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'Donnell
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA. [email protected]
PMID: 22420884 DOI: 10.1021/jm300094u
Abstract

Replacement 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 ↑ 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.

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