4I12

Design and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitors

Summary for 4I12

• Entry DOI: 10.2210/pdb4i12/pdb
• Related: 4HZI 4I0D 4I0E 4I0F 4I0G 4I0Z 4I10 4I1C
• Descriptor: Beta-secretase 1, 2-{(1S)-1-{[(1Z)-6-chloro-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]amino}-2-[2-propyl-4-(1H-pyrazol-4-yl)thiophen-3-yl]ethyl}pyrimidin-4(5H)-one, ZINC ION, ... (5 entities in total)
• Functional Keywords: aspartic protease, 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: 1
• Total formula weight: 46208.40

Authors

Lougheed, J.C.,Brecht, E.,Yao, N.H. (deposition date: 2012-11-19, release date: 2013-03-06, Last modification date: 2018-01-24)

Primary citation

Xu, Y.Z.,Yuan, S.,Bowers, S.,Hom, R.K.,Chan, W.,Sham, H.L.,Zhu, Y.L.,Beroza, P.,Pan, H.,Brecht, E.,Yao, N.,Lougheed, J.,Yan, J.,Tam, D.,Ren, Z.,Ruslim, L.,Bova, M.P.,Artis, D.R.
Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.
Bioorg.Med.Chem.Lett., 23:3075-3080, 2013

PubMed Abstract: Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.

PubMed: 23570791
DOI: 10.1016/j.bmcl.2013.03.009

Experimental method

X-RAY DIFFRACTION (1.78 Å)