Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trial...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Journal of medicinal chemistry 2013-07, Vol.56 (13), p.5261-5274
Hauptverfasser:	Probst, Gary, Aubele, Danielle L, Bowers, Simeon, Dressen, Darren, Garofalo, Albert W, Hom, Roy K, Konradi, Andrei W, Marugg, Jennifer L, Mattson, Matthew N, Neitzel, Martin L, Semko, Chris M, Sham, Hing L, Smith, Jenifer, Sun, Minghua, Truong, Anh P, Ye, Xiaocong M, Xu, Ying-zi, Dappen, Michael S, Jagodzinski, Jacek J, Keim, Pamela S, Peterson, Brian, Latimer, Lee H, Quincy, David, Wu, Jing, Goldbach, Erich, Ness, Daniel K, Quinn, Kevin P, Sauer, John-Michael, Wong, Karina, Zhang, Hongbin, Zmolek, Wes, Brigham, Elizabeth F, Kholodenko, Dora, Hu, Kang, Kwong, Grace T, Lee, Michael, Liao, Anna, Motter, Ruth N, Sacayon, Patricia, Santiago, Pamela, Willits, Christopher, Bard, Frédérique, Bova, Michael P, Hemphill, Susanna S, Nguyen, Lam, Ruslim, Lany, Tanaka, Kevin, Tanaka, Pearl, Wallace, William, Yednock, Ted A, Basi, Guriqbal S
Format:	Artikel
Sprache:	eng
Schlagworte:	Amyloid beta-Peptides - antagonists & inhibitors Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Area Under Curve Basic Helix-Loop-Helix Transcription Factors - genetics Dogs Dose-Response Relationship, Drug Drug Design Drug Stability Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Gene Expression - drug effects Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Homeodomain Proteins - genetics Humans Male Mice Microsomes, Liver - drug effects Microsomes, Liver - metabolism Models, Chemical Molecular Structure Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Quinolines - chemical synthesis Quinolines - pharmacokinetics Quinolines - pharmacology Rats Rats, Sprague-Dawley Receptors, Notch - antagonists & inhibitors Receptors, Notch - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides - pharmacology Time Factors Transcription Factor HES-1
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Schreiben Sie den ersten Kommentar!