Pyridazine-derived γ-secretase modulators

Zehong Wan; Adrian Hall; Yun Jin; Jia-Ning Xiang; Eric Yang; Andrew Eatherton; Beverley Smith; Guang Yang; Haihua Yu; Ju Wang; Liang Ye; Lit-Fui Lau; Ting Yang; William Mitchell; Wei Cai; Xiaomin Zhang; Yingxia Sang; Yonghui Wang; Zhaolong Tong; Ziqiang Cheng; Ishrut Hussain; John D Elliott; Yasuji Matsuoka

doi:10.1016/j.bmcl.2011.04.143

Pyridazine-derived γ-secretase modulators

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4016-9. doi: 10.1016/j.bmcl.2011.04.143. Epub 2011 May 13.

Affiliation

¹ Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201023, China. zehong.2.wan@gsk.com

PMID: 21636276
DOI: 10.1016/j.bmcl.2011.04.143

Abstract

SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism
Animals
Cell Survival
Cells, Cultured
Enzyme Activation / drug effects
Humans
Inhibitory Concentration 50
Pyridazines / chemical synthesis*
Pyridazines / chemistry
Pyridazines / pharmacology
Rats
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Pyridazines
pyridazine
Amyloid Precursor Protein Secretases