4B70: Aminoimidazoles As Bace-1 Inhibitors: From De Novo Design To Ab-lowering In Brain

Citation:
Abstract
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
PDB ID: 4B70Download
MMDB ID: 111209
PDB Deposition Date: 2012/8/16
Updated in MMDB: 2013/07
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4B70: monomeric; determined by author and by software (PISA)
Molecular Components in 4B70
Label Count Molecule
Protein (1 molecule)
1
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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