title: Pyridazine-derived γ-secretase modulators.
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.
authors.affiliation: Research and Development, GlaxoSmithKline Pharmaceuticals, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201023, China. zehong.2.wan@gsk.com
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Yun
authors.initials: Y
authors.lastname: Jin
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xiang
authors.forename: Eric
authors.initials: E
authors.lastname: Yang
authors.forename: Andrew
authors.initials: A
authors.lastname: Eatherton
authors.forename: Beverley
authors.initials: B
authors.lastname: Smith
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Haihua
authors.initials: H
authors.lastname: Yu
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Ye
authors.forename: Lit-Fui
authors.initials: LF
authors.lastname: Lau
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.forename: William
authors.initials: W
authors.lastname: Mitchell
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Sang
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhaolong
authors.initials: Z
authors.lastname: Tong
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: John D
authors.initials: JD
authors.lastname: Elliott
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D011724:Pyridazines; C062482:pyridazine; D053829:Amyloid Precursor Protein Secretases