Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718)

Thomas A Dineen; Kui Chen; Alan C Cheng; Katayoun Derakhchan; Oleg Epstein; Joel Esmay; Dean Hickman; Chuck E Kreiman; Isaac E Marx; Robert C Wahl; Paul H Wen; Matthew M Weiss; Douglas A Whittington; Stephen Wood; Robert T Fremeau Jr; Ryan D White; Vinod F Patel

doi:10.1021/jm5012676

Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718)

J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14.

Authors

Thomas A Dineen¹, Kui Chen, Alan C Cheng, Katayoun Derakhchan, Oleg Epstein, Joel Esmay, Dean Hickman, Chuck E Kreiman, Isaac E Marx, Robert C Wahl, Paul H Wen, Matthew M Weiss, Douglas A Whittington, Stephen Wood, Robert T Fremeau Jr, Ryan D White, Vinod F Patel

Affiliation

¹ Departments of Therapeutic Discovery, ‡Neuroscience, §Molecular Structure and Characterization, ∥Pharmacokinetics and Drug Metabolism, and ⊥Comparative Biology and Safety Sciences, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, and One Amgen Center Drive, Thousand Oaks, California 91320, United States.

PMID: 25363711
DOI: 10.1021/jm5012676

Abstract

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Benzopyrans / chemical synthesis*
Benzopyrans / pharmacology
Ether-A-Go-Go Potassium Channels / drug effects
HEK293 Cells
Humans
Inhibitory Concentration 50
Microsomes, Liver / metabolism
Protease Inhibitors / chemical synthesis*
Pyridines / chemical synthesis*
Pyridines / pharmacology
Rats, Sprague-Dawley
Spiro Compounds / chemical synthesis*
Spiro Compounds / pharmacology
Structure-Activity Relationship

Substances

(S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro(chromeno(2,3-b)pyridine-5,4'-oxazol)-2'-amine
Amyloid beta-Peptides
Benzopyrans
Ether-A-Go-Go Potassium Channels
KCNH1 protein, human
Protease Inhibitors
Pyridines
Spiro Compounds
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human

Associated data

PDB/4RCD