Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

被引：56

作者：

Albright, Charles F. ^{[1
]}

Dockens, Randy C. ^{[2
]}

Meredith, Jere E., Jr. ^{[1
]}

Olson, Richard E. ^{[1
]}

Slemmon, Randy ^{[2
]}

Lentz, Kimberley A. ^{[1
]}

Wang, Jun-Sheng ^{[3
]}

Denton, R. Rex ^{[1
]}

Pilcher, Gary ^{[1
]}

Rhyne, Paul W. ^{[3
]}

Raybon, Joseph J. ^{[1
]}

Barten, Donna M. ^{[1
]}

Burton, Catherine ^{[1
]}

Toyn, Jeremy H. ^{[1
]}

Sankaranarayanan, Sethu ^{[1
]}

Polson, Craig ^{[1
]}

Guss, Valerie ^{[1
]}

White, Randy ^{[4
]}

Simutis, Frank ^{[4
]}

Sanderson, Thomas ^{[4
]}

Gillman, Kevin W. ^{[1
]}

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

Bronson, Joanne ^{[1
]}

Sverdlov, Oleksandr ^{[3
]}

Huang, Shu-Pang ^{[3
]}

Castaneda, Lorna ^{[3
]}

Feldman, Howard ^{[1
]}

Coric, Vlad ^{[1
]}

Zaczek, Robert ^{[1
]}

Macor, John E. ^{[1
]}

Houston, John ^{[1
]}

Berman, Robert M. ^{[1
]}

Tong, Gary ^{[2
]}

机构：

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

[2] Bristol Myers Squibb Co, Hopewell Facil, Res & Dev, Pennington, NJ USA

[3] Bristol Myers Squibb Co, Res & Dev, Lawrenceville, NJ USA

[4] Bristol Myers Squibb Co, Dept Drug Safety Evaluat, Mt Vernon Facil, Res & Dev, Evansville, IN USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2013年 / 344卷 / 03期

关键词：

4 BASIC MODELS; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; HEALTHY-YOUNG; MOUSE MODEL; NOTCH; BMS-708163; DISCOVERY; MECHANISM; RECEPTOR;

D O I：

10.1124/jpet.112.199356

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid beta-peptide (A beta), generated by gamma-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, gamma-secretase inhibitors (GSIs) may lower brain A beta and offer a potential new approach to treat AD. As gamma-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of A beta and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) A beta levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF A beta 40 and A beta 42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF A beta 40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF A beta levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

引用

页码：686 / 695

页数：10

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