title: Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aβ peptides in vivo.
abstract: Accumulation of amyloid β (Aβ) in brain is a pathological hallmark of Alzheimer's disease (AD). Aβ is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by β- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aβ levels. Since γ-secretase targets many different substrates, selective inhibition of its cleavage of APP is believed to be critical in order to avoid undesirable side effects. γ-Secretase modulator (GSM) shifts the cleavage site on APP and production of amyloidogenic to non-amyloidogenic Aβ fragments. Since GSMs only modulate and do not block cleavage of γ-secretase substrates, they are believed less likely to produce untoward adverse reactions. Here, we report in vivo Aβ-lowering profiles of a pyridazine and a pyridine-derived GSM: GSM-C (Wan et al., 2011a) and GSM-D (Wan et al., 2011b). Both compounds reduced Aβ40 and Aβ42 productions, increased shorter Aβ fragments, and had little effect on Notch signaling (∼100-fold selective). They had excellent oral bioavailability (97.8% for GSM-C, ∼100% for GSM-D) and good brain permeability (free brain to free blood AUC ratio of 0.41 and 1.10 for GSM-C and GSM-D, respectively). Oral administration of these compounds in both acute and sub-chronic conditions reduced Aβ levels in plasma and brain in rats in a dose- and time-dependent manner. Therefore, GSM-C and GSM-D represent two GSMs that are orally bioavailable and brain-permeable. They could serve as excellent tools in the investigation of the role of Aβ peptides in AD pathogenesis.
authors.affiliation: Neurodegeneration Research, R&D China, GlaxoSmithKline, Shanghai 201203, China.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Huang
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Eatherton
authors.forename: William L
authors.initials: WL
authors.lastname: Mitchell
authors.forename: Na
authors.initials: N
authors.lastname: Rong
authors.forename: Liang
authors.initials: L
authors.lastname: Ye
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Yang
authors.forename: Shiyi
authors.initials: S
authors.lastname: Jin
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Jin
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Sang
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Edward R
authors.initials: ER
authors.lastname: Browne
authors.forename: David C
authors.initials: DC
authors.lastname: Harrison
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Lit-Fui
authors.initials: LF
authors.lastname: Lau
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D061251:Primary Cell Culture; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D060168:Thymocytes / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D011724:Pyridazines; D011725:Pyridines; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases