4FRS

Structure of BACE in complex with (S)-4-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium

Summary for 4FRS

• Entry DOI: 10.2210/pdb4frs/pdb
• Related: 4DJU 4DJV 4DJW 4DJX 4DJY
• Descriptor: Beta-secretase 1, (2Z,6S)-6-{3-chloro-5-[5-(prop-1-yn-1-yl)pyridin-3-yl]thiophen-2-yl}-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one (3 entities in total)
• Functional Keywords: alzheimer's, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 2
• Total formula weight: 88793.00

Authors

Orth, P. (deposition date: 2012-06-26, release date: 2012-08-08, Last modification date: 2024-11-20)

Primary citation

Stamford, A.W.,Scott, J.D.,Li, S.W.,Babu, S.,Tadesse, D.,Hunter, R.,Wu, Y.,Misiaszek, J.,Cumming, J.N.,Gilbert, E.J.,Huang, C.,McKittrick, B.A.,Hong, L.,Guo, T.,Zhu, Z.,Strickland, C.,Orth, P.,Voigt, J.H.,Kennedy, M.E.,Chen, X.,Kuvelkar, R.,Hodgson, R.,Hyde, L.A.,Cox, K.,Favreau, L.,Parker, E.M.,Greenlee, W.J.
Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS A(beta) Reduction
ACS Med Chem Lett, 3:897-902, 2012

PubMed Abstract: Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

PubMed: 23412139
DOI: 10.1021/ml3001165

Experimental method

X-RAY DIFFRACTION (1.7 Å)