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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.
- Source :
-
Journal of Medicinal Chemistry . 4/12/2012, Vol. 55 Issue 7, p3414-3424. 11p. - Publication Year :
- 2012
-
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 ↑ 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 55
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 145081064
- Full Text :
- https://doi.org/10.1021/jm300094u