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

被引：149

作者：

Gillman, Kevin W. ^{[1
]}

Starrett, John E., Jr. ^{[1
]}

Parker, Michael F. ^{[1
]}

Xie, Kai ^{[1
]}

Bronson, Joanne J. ^{[1
]}

Marcin, Lawrence R. ^{[1
]}

McElhone, Kate E. ^{[1
]}

Bergstrom, Carl P. ^{[1
]}

Mate, Robert A. ^{[1
]}

Williams, Richard ^{[4
]}

Meredith, Jere E., Jr. ^{[2
]}

Burton, Catherine R. ^{[2
]}

Barten, Donna M. ^{[2
]}

Toyn, Jeremy H. ^{[2
]}

Roberts, Susan B. ^{[2
]}

Lentz, Kimberley A. ^{[3
]}

Houston, John G. ^{[2
]}

Zaczek, Robert ^{[2
]}

Albright, Charles F. ^{[2
]}

Decicco, Carl P. ^{[1
]}

Macor, John E. ^{[1
]}

Olson, Richard E. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Neurosci Discovery Chem, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Co, Neurosci Discovery Biol, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Co, Metab & Pharmacokinet, Wallingford, CT 06492 USA

[4] Albany Mol Res Inc, Dept Med Chem, Albany, NY USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 03期

关键词：

gamma-Secretase; brain penetrant; oxadiazole; Alzheimer's; amyloid; clinical candidate; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; AMYLOID-BETA; AGONISTS; DIFFERENTIATION; DERIVATIVES; REDUCTIONS; BMS-299897; INDUCTION; PROTEINS;

D O I：

10.1021/ml1000239

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC(50) = 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.

引用

页码：120 / 124

页数：5

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