Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor
Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor
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DOI：
10.1021/ml1000239
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发表时间：
2010-06-01
影响因子：
4.2
通讯作者：
Olson, Richard E.
中科院分区：
文献类型：
--
作者：
Gillman, Kevin W.;Starrett, John E., Jr.;Olson, Richard E.
在我们努力开发用于治疗阿尔茨海默病的有效和选择性γ-分泌酶抑制剂的研究过程中，我们研究了一系列羧酰胺取代的磺胺类药物。基于效价、Notch/淀粉样β前体蛋白选择性和经口给药后的脑疗效进行优化，发现了4（BMS-708163）。化合物4是γ-分泌酶的有效抑制剂（A β 40 IC（50）= 0.30 nM），显示出对Notch的193倍选择性。在大鼠和犬中，经口给予4可持续显著降低脑、血浆和脑脊液中的A β 40水平。
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.