Discovery of N-ethylpyridine-2-carboxamide derivatives as a novel scaffold for orally active γ-secretase modulators

Ryuichi Sekioka; Shugo Honda; Eriko Honjo; Takayuki Suzuki; Hiroki Akashiba; Yasuyuki Mitani; Shingo Yamasaki

doi:10.1016/j.bmc.2019.115132

Discovery of N-ethylpyridine-2-carboxamide derivatives as a novel scaffold for orally active γ-secretase modulators

Bioorg Med Chem. 2020 Jan 1;28(1):115132. doi: 10.1016/j.bmc.2019.115132. Epub 2019 Nov 6.

Authors

Ryuichi Sekioka¹, Shugo Honda², Eriko Honjo², Takayuki Suzuki², Hiroki Akashiba², Yasuyuki Mitani², Shingo Yamasaki²

Affiliations

¹ Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ryuichi.sekioka@astellas.com.
² Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

PMID: 31767402
DOI: 10.1016/j.bmc.2019.115132

Abstract

Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer's disease because they can selectively decrease pathogenic amyloid-β42 (Aβ42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1'-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aβ42 levels with an IC₅₀ value of 0.091 µM in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aβ42 levels in mice.

Keywords: Alzheimer’s disease; Amyloid-beta peptide; Cytochrome P450 3A4; Gamma-secretase modulator.

MeSH terms

Administration, Oral
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Animals
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Male
Mice
Mice, Inbred Strains
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Pyridines / administration & dosage
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Enzyme Inhibitors
Pyridines
Amyloid Precursor Protein Secretases
pyridine