Stepwise Design of γ‑Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere

Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel...

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Veröffentlicht in:	Journal of medicinal chemistry 2020-08, Vol.63 (15), p.8534-8553
Hauptverfasser:	Rodríguez Sarmiento, Rosa María, Bissantz, Caterina, Bylund, Johan, Limberg, Anja, Neidhart, Werner, Jakob-Roetne, Roland, Wang, Lisha, Baumann, Karlheinz
Format:	Artikel
Sprache:	eng
Schlagworte:	Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Cell Line Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Humans Mice, Transgenic Models, Molecular Neurons - drug effects Neurons - metabolism
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