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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

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

Gary Probst, Danielle L Aubele, Simeon Bowers, Darren Dressen, Albert W Garofalo, Roy K Hom, Andrei W Konradi, Jennifer L Marugg, Matthew N Mattson, Martin L Neitzel, Chris M Semko, Hing L Sham, Jenifer Smith, etc.

J Med Chem. 2013 Jul 11;56(13):5261-74.

PMID: 23713656

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1333990843	ELND006		1333990-84-3	Price
AP769169279	Begacestat		769169-27-9	Price

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