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4FM7

Crystal Structure of BACE with Compound 14g

Summary for 4FM7
Entry DOI10.2210/pdb4fm7/pdb
DescriptorBeta-secretase 1, 4-{[(5R,7S)-1-(3-fluorophenyl)-3,7-dimethyl-2,2-dioxido-2-thia-1,3,8-triazaspiro[4.5]dec-8-yl]methyl}-2-(propan-2-yloxy)phenol, ZINC ION, ... (4 entities in total)
Functional Keywordsaspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationMembrane; Single-pass type I membrane protein: P56817
Total number of polymer chains1
Total formula weight45765.14
Authors
Vajdos, F.F.,Varghese, A.H. (deposition date: 2012-06-15, release date: 2012-10-03, Last modification date: 2024-11-06)
Primary citationBrodney, M.A.,Barreiro, G.,Ogilvie, K.,Hajos-Korcsok, E.,Murray, J.,Vajdos, F.,Ambroise, C.,Christoffersen, C.,Fisher, K.,Lanyon, L.,Liu, J.,Nolan, C.E.,Withka, J.M.,Borzilleri, K.A.,Efremov, I.,Oborski, C.E.,Varghese, A.,O'Neill, B.T.
Spirocyclic sulfamides as beta-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors.
J.Med.Chem., 55:9224-9239, 2012
Cited by
PubMed Abstract: β-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aβ(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aβ lowering versus that observed in wild-type (WT) mouse at an equivalent dose.
PubMed: 22984865
DOI: 10.1021/jm3009426
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.56 Å)
Structure validation

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