4fm8 | pdb_00004fm8
Crystal Structure of BACE with Compound 12a
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedbeta-Secretase (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 CNS penetration by minimizing hydrogen bond donors (HBD) 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 analogs 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 AbetaX-40 levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies in the P-gp knock-out mouse provided evidence that efflux transporters impacted the amount of Abeta lowering versus that observed in wild-type (WT) mouse at equivalent dose. Spirocyclic Sulfamides as 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.,Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray JC, Vajdos FF, Ambroise C, Christoffersen C, Fisher KE, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov IV, Oborski CE, Varghese AH, O'Neill BT J Med Chem. 2012 Sep 17. PMID:22984865[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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