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.
Ryuichi Sekioka  1 ,  Shugo Honda  2 ,  Eriko Honjo  2 ,  Takayuki Suzuki  2 ,  Hiroki Akashiba  2 ,  Yasuyuki Mitani  2 ,  Shingo Yamasaki  2
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
  • 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.
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