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

• Published in: Journal of medicinal chemistry 2013-07, Vol.56 (13), p.5261-5274
• Main Authors: 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: Article
• Language: English
• Subjects: 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301741t

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 trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.