Abstract
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / metabolism
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Blood-Brain Barrier / physiology
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Brain / metabolism
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Crystallography, X-Ray
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Dogs
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Drug Stability
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / pharmacokinetics
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Humans
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Madin Darby Canine Kidney Cells
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Male
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Mice
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Microsomes, Liver / metabolism
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Molecular Structure
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Protein Binding
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Pyrazines / chemical synthesis
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology*
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Rats
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Structure-Activity Relationship
Substances
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Heterocyclic Compounds, 2-Ring
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LY3202626
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Protease Inhibitors
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Pyrazines
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Pyrroles
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human