Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors.
Alzheimer's disease (AD) is the most common form of dementia. In an AD patient's brain, senile plaques and neurofibrillary tangles, the abnormal aggregates of amyloid β (Aβ) peptide and tau protein, are observed as the two major hallmarks of this disease. To develop a new drug for treatment of AD, we have designed and synthesized a series of curcumin derivatives and evaluated their inhibitory activities against both tau and Aβ aggregation. In this study, we describe the development of the more potent aggregation inhibitor 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) phenyl] ethenyl]-1H-pyrazole (compound 4, PE859). This compound has a better pharmacokinetic profile and pharmacological efficacy in vivo than curcumin, making it suitable as a drug for AD.
Graduate School of Brain Science, Doshisha University, 4-1-1 Kizugawadai, Kizugawa, Kyoto 619-0225, Japan; Pharma Eight Co., Ltd., Creation Core Kyoto Mikuruma, 448-5 Kajii-cho, Kamigyo-ku, Kyoto 602-0841, Japan. Electronic address: jt-liaay@mail.doshisha.ac.jp.
Michiaki
M
Okuda
ChemGenesis Inc., 4-10-2, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
Ichiro
I
Hijikuro
Graduate School of Brain Science, Doshisha University, 4-1-1 Kizugawadai, Kizugawa, Kyoto 619-0225, Japan; Pharma Eight Co., Ltd., Creation Core Kyoto Mikuruma, 448-5 Kajii-cho, Kamigyo-ku, Kyoto 602-0841, Japan.
Yuki
Y
Fujita
Pharma Eight Co., Ltd., Creation Core Kyoto Mikuruma, 448-5 Kajii-cho, Kamigyo-ku, Kyoto 602-0841, Japan.
Takayuki
T
Teruya
Pharma Eight Co., Ltd., Creation Core Kyoto Mikuruma, 448-5 Kajii-cho, Kamigyo-ku, Kyoto 602-0841, Japan.
Hirochika
H
Kawakami
Yokohama College of Pharmacy, Natural Product Chemistry & Pharmaceutical Research Center, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan.
Takashi
T
Takahashi
Graduate School of Brain Science, Doshisha University, 4-1-1 Kizugawadai, Kizugawa, Kyoto 619-0225, Japan.
Hachiro
H
Sugimoto
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000187:drug effects; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D003474:Curcumin
Aggregation inhibitor; Alzheimer’s disease; Amyloid β; Curcumin; Tau