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Pyridine-derived γ-secretase modulators. 2011
Zehong Wan, and
Adrian Hall, and
Yingxia Sang, and
Jia-Ning Xiang, and
Eric Yang, and
Beverley Smith, and
David C Harrison, and
Guang Yang, and
Haihua Yu, and
Helen S Price, and
Jian Wang, and
Julie Hawkins, and
Lit-Fui Lau, and
Matthew R Johnson, and
Tina Li, and
Wei Zhao, and
William L Mitchell, and
Xiaobo Su, and
Xiaomin Zhang, and
Yanjiao Zhou, and
Yun Jin, and
Zhaolong Tong, and
Ziqiang Cheng, and
Ishrut Hussain, and
John D Elliott, and
Yasuji Matsuoka
Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201023, China. Zehong.2.Wan@gsk.com
SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral.
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