Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity

Tobias Ginman; Jenny Viklund; Jonas Malmström; Jan Blid; Rikard Emond; Rickard Forsblom; Anh Johansson; Annika Kers; Fredrik Lake; Fernando Sehgelmeble; Karin J Sterky; Margareta Bergh; Anders Lindgren; Patrik Johansson; Fredrik Jeppsson; Johanna Fälting; Ylva Gravenfors; Fredrik Rahm

doi:10.1021/jm3011349

Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity

J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May 20.

Authors

Tobias Ginman¹, Jenny Viklund, Jonas Malmström, Jan Blid, Rikard Emond, Rickard Forsblom, Anh Johansson, Annika Kers, Fredrik Lake, Fernando Sehgelmeble, Karin J Sterky, Margareta Bergh, Anders Lindgren, Patrik Johansson, Fredrik Jeppsson, Johanna Fälting, Ylva Gravenfors, Fredrik Rahm

Affiliation

¹ Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden.

PMID: 23126626
DOI: 10.1021/jm3011349

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 μM 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.

MeSH terms

Amidines / chemical synthesis*
Amidines / chemistry
Amidines / pharmacology
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Brain / metabolism
CHO Cells
Cell Line, Tumor
Cell Membrane Permeability
Computer Simulation
Cricetinae
Crystallography, X-Ray
Dogs
Drug Stability
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Ether-A-Go-Go Potassium Channels / metabolism
Female
Guanidines / chemical synthesis*
Guanidines / chemistry
Guanidines / pharmacology
Humans
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred C57BL
Protein Conformation
Quantitative Structure-Activity Relationship
Stereoisomerism

Substances

Amidines
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Guanidines
KCNH2 protein, human
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human

Associated data

PDB/4B70
PDB/4B72
PDB/4B77
PDB/4B78