Novel orally bioavailable γ-secretase inhibitors with excellent in vivo activity

…, LC Cooper, T Harrison, A Madin, J Mistry…

Index: Keown, Linda E.; Collins, Ian; Cooper, Laura C.; Harrison, Timothy; Madin, Andrew; Mistry, Jayesh; Reilly, Michael; Shaimi, Mohamed; Welch, Christopher J.; Clarke, Earl E.; Lewis, Huw D.; Wrigley, Jonathan D. J.; Best, Jonathan D.; Murray, Fraser; Shearman, Mark S. Journal of Medicinal Chemistry, 2009 , vol. 52, # 11 p. 3441 - 3444

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Citation Number: 14

Abstract

The development of potent γ-secretase inhibitors having substituted heterocycles attached to a benzobicyclo [4.2. 1] nonane core is described. This work led to the identification of [6 S, 9 R, 11 R]-2′, 3′, 4′, 5, 5′, 6, 7, 8, 9, 10-decahydro-2-(5-(4-fluorophenyl)-1- methylpyrazol-3-yl)-5′-(2, 2, 2-trifluoroethyl) spiro [6, 9-methanobenzocyclooctene-11, 3′- [1, 2, 5] thiadiazole] 1′, 1′-dioxide (16), which has excellent in vitro potency (0.06 nM) ...