| Autor: |
Brodney MA; Department of Neuroscience, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michael.a.brodney@pfizer.com, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray J, Vajdos F, Ambroise C, Christoffersen C, Fisher K, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov I, Oborski CE, Varghese A, O'Neill BT |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2012 Nov 08; Vol. 55 (21), pp. 9224-39. Date of Electronic Publication: 2012 Oct 08. |
| DOI: |
10.1021/jm3009426 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
