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.

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, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.

DOI: 10.1021/jm301741t

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@article{Probst2013DiscoveryO, title={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.}, author={G. Duane Probst and Danielle L Aubele and Simeon G Bowers and Darren B Dressen and Albert William Garofalo and Roy K. Hom and Andrei William Konradi and Jennifer L Marugg and Matthew N Mattson and Martin Neitzel and Chris M Semko and Hing Leung Sham and Jenifer L Smith and Minghua Sun and Anh P Truong and Xiaocong Michael Ye and Ying-zi Xu and Michael S Dappen and Jacek Jerzy Jagodzinski and Pamela S Keim and Brian Peterson and Lee H Latimer and David A Quincy and Jing Wu and Erich G Goldbach and Daniel K. Ness and Kevin Quinn and J Sauer and Karina L. Wong and Hong-bin Zhang and Wes Zmolek and Elizabeth F. Brigham and Dora Kholodenko and Kang Hu and Grace T Kwong and Michael Lee and Anna Liao and Ruth N Motter and Patricia Sacayon and Pamela Santiago and Christopher Willits and Fr{\'e}d{\'e}rique Bard and Michael P. Bova and Susanna S Hemphill and Lam M. Nguyen and Lany Ruslim and Kevin Tanaka and Pearl Tanaka and William Wallace and T . A . Yednock and Guriqbal S. Basi}, journal={Journal of medicinal chemistry}, year={2013}, volume={56 13}, pages={5261-74} }