Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

K.W. Gillman; J.E. Starrett; M.F. Parker; K. Xie; J.J. Bronson; L.R. Marcin; K.E. McElhone; C.P. Bergstrom; R.A. Mate; Richard Williams; J.E. Meredith; C.R. Burton; D.M. Barten; J.H. Toyn; S.B. Roberts; K.A. Lentz; J.G. Houston; R. Zaczek; C.F. Albright; C.P. Decicco; J.E. Macor; R.E. Olson

doi:10.1021/ml1000239

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

K.W. Gillman, J.E. Starrett, M.F. Parker, K. Xie, J.J. Bronson, L.R. Marcin, K.E. McElhone, C.P. Bergstrom, R.A. Mate, Richard Williams, J.E. Meredith, C.R. Burton, D.M. Barten, J.H. Toyn, S.B. Roberts, K.A. Lentz, J.G. Houston, R. Zaczek, C.F. Albright, C.P. DeciccoJ.E. Macor, R.E. Olson

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Abstract

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Original language	English
Pages (from-to)	120-124
Number of pages	5
Journal	ACS MEDICINAL CHEMISTRY LETTERS
Volume	1
Issue number	3
DOIs	https://doi.org/10.1021/ml1000239
Publication status	Published - 10 Jun 2010

ASJC Scopus subject areas

Organic Chemistry
Drug Discovery
Biochemistry

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10.1021/ml1000239

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Gillman, K. W., Starrett, J. E., Parker, M. F., Xie, K., Bronson, J. J., Marcin, L. R., McElhone, K. E., Bergstrom, C. P., Mate, R. A., Williams, R., Meredith, J. E., Burton, C. R., Barten, D. M., Toyn, J. H., Roberts, S. B., Lentz, K. A., Houston, J. G., Zaczek, R., Albright, C. F., ... Olson, R. E. (2010). Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. ACS MEDICINAL CHEMISTRY LETTERS, 1(3), 120-124. https://doi.org/10.1021/ml1000239

Gillman, K.W. ; Starrett, J.E. ; Parker, M.F. ; Xie, K. ; Bronson, J.J. ; Marcin, L.R. ; McElhone, K.E. ; Bergstrom, C.P. ; Mate, R.A. ; Williams, Richard ; Meredith, J.E. ; Burton, C.R. ; Barten, D.M. ; Toyn, J.H. ; Roberts, S.B. ; Lentz, K.A. ; Houston, J.G. ; Zaczek, R. ; Albright, C.F. ; Decicco, C.P. ; Macor, J.E. ; Olson, R.E. / Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. In: ACS MEDICINAL CHEMISTRY LETTERS. 2010 ; Vol. 1, No. 3. pp. 120-124.

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title = "Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor",

abstract = "During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.",

author = "K.W. Gillman and J.E. Starrett and M.F. Parker and K. Xie and J.J. Bronson and L.R. Marcin and K.E. McElhone and C.P. Bergstrom and R.A. Mate and Richard Williams and J.E. Meredith and C.R. Burton and D.M. Barten and J.H. Toyn and S.B. Roberts and K.A. Lentz and J.G. Houston and R. Zaczek and C.F. Albright and C.P. Decicco and J.E. Macor and R.E. Olson",

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doi = "10.1021/ml1000239",

language = "English",

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Gillman, KW, Starrett, JE, Parker, MF, Xie, K, Bronson, JJ, Marcin, LR, McElhone, KE, Bergstrom, CP, Mate, RA, Williams, R, Meredith, JE, Burton, CR, Barten, DM, Toyn, JH, Roberts, SB, Lentz, KA, Houston, JG, Zaczek, R, Albright, CF, Decicco, CP, Macor, JE & Olson, RE 2010, 'Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor', ACS MEDICINAL CHEMISTRY LETTERS, vol. 1, no. 3, pp. 120-124. https://doi.org/10.1021/ml1000239

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. / Gillman, K.W.; Starrett, J.E.; Parker, M.F.; Xie, K.; Bronson, J.J.; Marcin, L.R.; McElhone, K.E.; Bergstrom, C.P.; Mate, R.A.; Williams, Richard; Meredith, J.E.; Burton, C.R.; Barten, D.M.; Toyn, J.H.; Roberts, S.B.; Lentz, K.A.; Houston, J.G.; Zaczek, R.; Albright, C.F.; Decicco, C.P.; Macor, J.E.; Olson, R.E.

In: ACS MEDICINAL CHEMISTRY LETTERS, Vol. 1, No. 3, 10.06.2010, p. 120-124.

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

TY - JOUR

T1 - Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

AU - Gillman, K.W.

AU - Starrett, J.E.

AU - Parker, M.F.

AU - Xie, K.

AU - Bronson, J.J.

AU - Marcin, L.R.

AU - McElhone, K.E.

AU - Bergstrom, C.P.

AU - Mate, R.A.

AU - Williams, Richard

AU - Meredith, J.E.

AU - Burton, C.R.

AU - Barten, D.M.

AU - Toyn, J.H.

AU - Roberts, S.B.

AU - Lentz, K.A.

AU - Houston, J.G.

AU - Zaczek, R.

AU - Albright, C.F.

AU - Decicco, C.P.

AU - Macor, J.E.

AU - Olson, R.E.

PY - 2010/6/10

Y1 - 2010/6/10

N2 - During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

AB - During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

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U2 - 10.1021/ml1000239

DO - 10.1021/ml1000239

M3 - Article

VL - 1

SP - 120

EP - 124

JO - ACS MEDICINAL CHEMISTRY LETTERS

JF - ACS MEDICINAL CHEMISTRY LETTERS

SN - 1948-5875

IS - 3

ER -

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

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