Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing

Philippe G. Nantermet; Hemaka A. Rajapakse; Mathew G. Stanton; Shaun R. Stauffer; James C. Barrow; Allison R. Gregro; Keith P. Moore; Melissa A. Steinbeiser; John Swestock; Harold G. Selnick; Samuel L. Graham; Georgia B. McGaughey; Dennis Colussi; Ming Tain Lai; Sethu Sankaranarayanan; Adam J. Simon; Sanjeev Munshi; Jacquelynn J. Cook; Marie A. Holahan; Maria S. Michener; Joseph P. Vacca

doi:10.1002/cmdc.200800308

Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing

Philippe G. Nantermet, Hemaka A. Rajapakse, Mathew G. Stanton, Shaun R. Stauffer, James C. Barrow, Allison R. Gregro, Keith P. Moore, Melissa A. Steinbeiser, John Swestock, Harold G. Selnick, Samuel L. Graham, Georgia B. McGaughey, Dennis Colussi, Ming Tain Lai, Sethu Sankaranarayanan, Adam J. Simon, Sanjeev Munshi, Jacquelynn J. Cook, Marie A. Holahan, Maria S. MichenerJoseph P. Vacca

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Incorporation of an isonicotinic core containing a P3 methylcyclopropyl group into our previously reported ox-adiazolyl tertiary carbinamine based BACE-1 inhibitors has led to the identification of the exquisitely potent inhibitor 6, which displays good permeability and low susceptibility to the P-gp efflux pump. Upon co-dosing with CYP 3A4 inhibitor ritonavir, tertiary carbinamine 6 was found to be orally bioavailable. Following twice daily oral administration to monkeys, it was shown to penetrate the CNS and lower Aβ₄₂ levels in the CSF by >40% over the course of a 3 day experiment. Further structural improvements aimed at optimization of pharmacokinetics and brain penetration will be the subject of future work, as will studies of the impact of central BACE-1 inhibitor-mediated Aβ₄₂ lowering on cognition.

Original language	English (US)
Pages (from-to)	37-40
Number of pages	4
Journal	ChemMedChem
Volume	4
Issue number	1
DOIs	https://doi.org/10.1002/cmdc.200800308
State	Published - Jan 12 2009
Externally published	Yes

Keywords

Alzheimer's disease
Aβ reduction
BACE-1
Inhibitors
β-secretase

ASJC Scopus subject areas

Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Molecular Medicine
Biochemistry
Pharmacology
Organic Chemistry

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Nantermet, P. G., Rajapakse, H. A., Stanton, M. G., Stauffer, S. R., Barrow, J. C., Gregro, A. R., Moore, K. P., Steinbeiser, M. A., Swestock, J., Selnick, H. G., Graham, S. L., McGaughey, G. B., Colussi, D., Lai, M. T., Sankaranarayanan, S., Simon, A. J., Munshi, S., Cook, J. J., Holahan, M. A., ... Vacca, J. P. (2009). Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing. ChemMedChem, 4(1), 37-40. https://doi.org/10.1002/cmdc.200800308

Nantermet, PG, Rajapakse, HA, Stanton, MG, Stauffer, SR, Barrow, JC, Gregro, AR, Moore, KP, Steinbeiser, MA, Swestock, J, Selnick, HG, Graham, SL, McGaughey, GB, Colussi, D, Lai, MT, Sankaranarayanan, S, Simon, AJ, Munshi, S, Cook, JJ, Holahan, MA, Michener, MS & Vacca, JP 2009, 'Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing', ChemMedChem, vol. 4, no. 1, pp. 37-40. https://doi.org/10.1002/cmdc.200800308

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abstract = "Incorporation of an isonicotinic core containing a P3 methylcyclopropyl group into our previously reported ox-adiazolyl tertiary carbinamine based BACE-1 inhibitors has led to the identification of the exquisitely potent inhibitor 6, which displays good permeability and low susceptibility to the P-gp efflux pump. Upon co-dosing with CYP 3A4 inhibitor ritonavir, tertiary carbinamine 6 was found to be orally bioavailable. Following twice daily oral administration to monkeys, it was shown to penetrate the CNS and lower Aβ42 levels in the CSF by >40% over the course of a 3 day experiment. Further structural improvements aimed at optimization of pharmacokinetics and brain penetration will be the subject of future work, as will studies of the impact of central BACE-1 inhibitor-mediated Aβ42 lowering on cognition.",

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AU - Sankaranarayanan, Sethu

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AU - Munshi, Sanjeev

AU - Cook, Jacquelynn J.

AU - Holahan, Marie A.

AU - Michener, Maria S.

AU - Vacca, Joseph P.

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Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing

Abstract

Keywords

ASJC Scopus subject areas

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