Aminostyrylbenzofuran directly reduces oligomeric amyloid-β and reverses cognitive deficits in Alzheimer transgenic mice.
Alzheimer's disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-β into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-β aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4-dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-β oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimer's disease symptoms, KMS88009 significantly reduced assembly of amyloid-β oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimer's disease.
Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd., Hwaseong-si, Gyonggi-do, Republic of Korea; Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Sang-Hyun
SH
Lee
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Biological Chemistry Program, University of Science and Technology (UST), Daejeon, Republic of Korea.
YoungSoo
Y
Kim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Biological Chemistry Program, University of Science and Technology (UST), Daejeon, Republic of Korea; Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Republic of Korea.
Hye Yun
HY
Kim
Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd., Hwaseong-si, Gyonggi-do, Republic of Korea.
Young Hoon
YH
Kim
Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd., Hwaseong-si, Gyonggi-do, Republic of Korea.
Maeng Sup
MS
Kim
College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
Jae Yang
JY
Kong
Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Mun-Han
MH
Lee
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Dong Jin
DJ
Kim
Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd., Hwaseong-si, Gyonggi-do, Republic of Korea.
Young Gil
YG
Ahn
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D001572:Benzofurans