Journal of Medicinal Chemistry p. 4476 - 4504 (2018)
Update date:2022-08-29
Topics:
O'Neill, Brian T.
Beck, Elizabeth M.
Butler, Christopher R.
Nolan, Charles E.
Gonzales, Cathleen
Zhang, Lei
Doran, Shawn D.
Lapham, Kimberly
Buzon, Leanne M.
Dutra, Jason K.
Barreiro, Gabriela
Hou, Xinjun
Martinez-Alsina, Luis A.
Rogers, Bruce N.
Villalobos, Anabella
Murray, John C.
Ogilvie, Kevin
Lachapelle, Erik A.
Chang, Cheng
Lanyon, Lorraine F.
Steppan, Claire M.
Robshaw, Ashley
Hales, Katherine
Boucher, Germaine G.
Pandher, Karamjeet
Houle, Christopher
Ambroise, Claude W.
Karanian, David
Riddell, David
Bales, Kelly R.
Brodney, Michael A.
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.
View MoreContact:+86-10-67147360/67107388
Address:No.18 Guangming Zhongjie, Chongwen District, Beijing, 100061, China
LIAONING DMSO CHEMICALS CO.,LTD.
website:http://www.chinadmso.com
Contact:+86-427-6503033
Address:FLOOR 16, BLOCK A, FINANCIAL SQUARE, XINGLONGTAI DISTRICT, PANJIN CITY, LIAONING P.R. CHINA
Changzhou Medi-tech Bioscientific Co., Ltd.
Contact:86-519-83246372
Address:Number 115 Menghedadao Road, Changzhou, Jiangsu, China
Jinan Hongfangde Pharmatech Co.,Ltd
Contact:86-531-88870908
Address:F Bldg. West Unit North Area of Univ. Tech. Garden Xinyu Rd. Jinan New & High Tech Industry Development Zone Shandong, China
Dalian RSD International Trade Co.,Ltd.
Contact:86-22-60875058 58610575
Address:Wantong International Areas, Hongqiao District, Tianjin, China.China
Doi:10.1016/j.tetlet.2019.151123
(2019)Doi:10.1007/s10593-007-0125-7
(2007)Doi:10.1016/j.bmcl.2021.127917
(2021)Doi:10.1007/s11743-010-1213-8
(2011)Doi:10.1002/anie.201203374
(2012)Doi:10.1039/c6gc01922f
(2017)