Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 58; no. 22; pp. 8806 - 8817
• Main Authors: Zhao, Zhiqiang, Pissarnitski, Dmitri A, Josien, Hubert B, Wu, Wen-Lian, Xu, Ruo, Li, Hongmei, Clader, John W, Burnett, Duane A, Terracina, Giuseppe, Hyde, Lynn, Lee, Julie, Song, Lixin, Zhang, Lili, Parker, Eric M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.11.2015; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Biological Availability; Central Nervous System - drug effects; Central Nervous System - metabolism; Chemistry, Medicinal; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Drug Discovery - methods; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; HEK293 Cells; Humans; Life Sciences & Biomedicine; Molecular Conformation; Pharmacology & Pharmacy; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Sulfonamides - pharmacology; MILD; NOTCH; SULFONES; DIFFERENTIATION; ALZHEIMERS-DISEASE; MODULATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00774

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer’s disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a­(−) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.