The evolution of amidine-based brain penetrant BACE1 inhibitors.
Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.
Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address: doehlric@its.jnj.com.
Daniel
D
Oehlrich
Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Hana
H
Prokopcova
Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Harrie J M
HJ
Gijsen
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000578:Amidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008958:Models, Molecular
D000578:Amidines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s; Amyloid; BACE; BACE1; Inhibitor