Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2

Liping H Pettus; Matthew P Bourbeau; Jodi Bradley; Michael D Bartberger; Kui Chen; Dean Hickman; Michael Johnson; Qingyian Liu; James R Manning; Adrian Nanez; Aaron C Siegmund; Paul H Wen; Douglas A Whittington; Jennifer R Allen; Stephen Wood

doi:10.1021/acs.jmedchem.9b01034

Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2

J Med Chem. 2020 Mar 12;63(5):2263-2281. doi: 10.1021/acs.jmedchem.9b01034. Epub 2019 Oct 18.

Authors

Liping H Pettus, Matthew P Bourbeau, Jodi Bradley, Michael D Bartberger, Kui Chen, Dean Hickman, Michael Johnson, Qingyian Liu, James R Manning, Adrian Nanez, Aaron C Siegmund, Paul H Wen, Douglas A Whittington, Jennifer R Allen, Stephen Wood

PMID: 31589043
DOI: 10.1021/acs.jmedchem.9b01034

Abstract

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC₅₀ BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ₄₀ levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.

MeSH terms

Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / cerebrospinal fluid
Amyloid beta-Peptides / metabolism
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Brain / drug effects
Brain / metabolism
Cyclopropanes / chemistry
Cyclopropanes / pharmacokinetics
Cyclopropanes / pharmacology*
Cyclopropanes / therapeutic use
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / therapeutic use
Humans
Male
Mice
Models, Molecular
Peptide Fragments / cerebrospinal fluid
Peptide Fragments / metabolism
Rats, Sprague-Dawley
Thiazines / chemistry
Thiazines / pharmacokinetics
Thiazines / pharmacology*
Thiazines / therapeutic use

Substances

Amyloid beta-Peptides
Bace2 protein, mouse
Cyclopropanes
Enzyme Inhibitors
Peptide Fragments
Thiazines
amyloid beta-protein (1-40)
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human
Bace1 protein, mouse