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

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 1; pp. 115132 - 115142
• Main Authors: Sekioka, Ryuichi, Honda, Shugo, Honjo, Eriko, Suzuki, Takayuki, Akashiba, Hiroki, Mitani, Yasuyuki, Yamasaki, Shingo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2020; Elsevier
• Subjects: Administration, Oral; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - metabolism; Amyloid-beta peptide; Animals; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytochrome P450 3A4; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gamma-secretase modulator; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred Strains; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; Alzheimer’s disease; Gamma-secretase modulator; Amyloid-beta peptide; Cytochrome P450 3A4; AMYLOID PROTEIN; A-BETA-42; ALZHEIMERS-DISEASE; INHIBITORS; Alzheimer's disease
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.115132

[Display omitted] 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.