title: Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity.
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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ginman
authors.forename: Jenny
authors.initials: J
authors.lastname: Viklund
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmström
authors.forename: Jan
authors.initials: J
authors.lastname: Blid
authors.forename: Rikard
authors.initials: R
authors.lastname: Emond
authors.forename: Rickard
authors.initials: R
authors.lastname: Forsblom
authors.forename: Anh
authors.initials: A
authors.lastname: Johansson
authors.forename: Annika
authors.initials: A
authors.lastname: Kers
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lake
authors.forename: Fernando
authors.initials: F
authors.lastname: Sehgelmeble
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Sterky
authors.forename: Margareta
authors.initials: M
authors.lastname: Bergh
authors.forename: Anders
authors.initials: A
authors.lastname: Lindgren
authors.forename: Patrik
authors.initials: P
authors.lastname: Johansson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.forename: Ylva
authors.initials: Y
authors.lastname: Gravenfors
authors.forename: Fredrik
authors.initials: F
authors.lastname: Rahm
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D003198:Computer Simulation; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004285:Dogs; D004355:Drug Stability; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D000578:Amidines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006146:Guanidines; C000606913:KCNH2 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human