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

Stepan, Antonia F.; Subramanyam, Chakrapani; Efremov, Ivan V.; Dutra, Jason K.; O’Sullivan, Theresa J.; DiRico, Kenneth J.; McDonald, W. Scott; Won, Annie; Dorff, Peter H.; Nolan, Charles E.; Becker, Stacey L.; Pustilnik, Leslie R.; Riddell, David R.; Kauffman, Gregory W.; Kormos, Bethany L.; Zhang, Liming; Lu, Yasong; Capetta, Steven H.; Green, Michael E.; Karki, Kapil; Sibley, Evelyn; Atchison, Kevin P.; Hallgren, Andrew J.; Oborski, Christine E.; Robshaw, Ashley E.; Sneed, Blossom; O’Donnell, Christopher J.

doi:10.1021/jm300094u

Cited by 468

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

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

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Stepan, Antonia F., Subramanyam, Chakrapani, Efremov, Ivan V., Dutra, Jason K., O’Sullivan, Theresa J., DiRico, Kenneth J., McDonald, W. Scott, Won, Annie, Dorff, Peter H., Nolan, Charles E., Becker, Stacey L., Pustilnik, Leslie R., Riddell, David R., Kauffman, Gregory W., Kormos, Bethany L., Zhang, Liming, Lu, Yasong, Capetta, Steven H., Green, Michael E., Karki, Kapil, Sibley, Evelyn, Atchison, Kevin P., Hallgren, Andrew J., Oborski, Christine E., Robshaw, Ashley E., Sneed, Blossom, O’Donnell, Christopher J.·2012·Journal of Medicinal Chemistry

DOI 10.1021/jm300094u

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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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Authors: Stepan, A. F., Subramanyam, C., Efremov, I. V., Dutra, J. K., O’Sullivan, T. J., DiRico, K. J., McDonald, W. S., Won, A., Dorff, P. H., Nolan, C. E., Becker, S. L., Pustilnik, L. R., Riddell, D. R., Kauffman, G. W., Kormos, B. L., Zhang, L., Lu, Y., Capetta, S. H., Green, M. E., Karki, K., Sibley, E., Atchison, K. P., Hallgren, A. J., Oborski, C. E., Robshaw, A. E., Sneed, B., & O’Donnell, C. J.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2012-03-29
Volume: 55
Issue: 7
Pages: 3414-3424
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm300094u
OpenAlex: W2100446581
Cited by: 468
References: 30
FWCI: 4.15
Type: journal article
Language: en
Open access: green

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This page: CoChat. (2026). Citation check: 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. https://app.cochat.ai/papers/10.1021/jm300094u
The paper: Stepan, A. F., Subramanyam, C., Efremov, I. V., Dutra, J. K., O’Sullivan, T. J., DiRico, K. J., McDonald, W. S., Won, A., Dorff, P. H., Nolan, C. E., Becker, S. L., Pustilnik, L. R., Riddell, D. R., Kauffman, G. W., Kormos, B. L., Zhang, L., Lu, Y., Capetta, S. H., Green, M. E., . . . O’Donnell, C. J. (2012). 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 of Medicinal Chemistry. https://doi.org/10.1021/jm300094u

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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

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