Discovery of (R)-4-Cyclopropyl-7, 8-difluoro-5-(4-(trifluoromethyl) phenylsulfonyl)-4, 5-dihydro-1 H-pyrazolo [4, 3-c] quinoline (ELND006) and (R)-4-Cyclopropyl-8- …

…, S Bowers, D Dressen, AW Garofalo…

Index: 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, Frederique; Bova, Michael P.; Hemphill, Susanna S.; Nguyen, Lam; Ruslim, Lany; Tanaka, Kevin; Tanaka, Pearl; Wallace, William; Yednock, Ted A.; Basi, Guriqbal S. Journal of Medicinal Chemistry, 2013 , vol. 56, # 13 p. 5261 - 5274

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Citation Number: 12

Abstract

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 ...