Design and discovery of C2-fluoroalkyl iminothiazine dioxides as BACE inhibitors.

Autor: Taoka BM; Department of Discovery Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Wu WL; Department of Discovery Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Hao J; Department of Discovery Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Dolmaski M; Department of Discovery Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Wang H; Department of Computational and Structural Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Levorse D; Department of Preclinical Development, MRL, Merck & Co. Inc., 126 E. Lincoln Ave., Rahway, NJ 07065, USA., Orth P; Department of Computational and Structural Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Hyde LA; Department of Neuroscience, Safety and Laboratory Animal Research, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Smith B; Department of Safety and Laboratory Animal Research MRL, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Michener MS; Department of Safety and Laboratory Animal Research MRL, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Kennedy ME; Department of Neuroscience, Safety and Laboratory Animal Research, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Parker EM; Department of Neuroscience, Safety and Laboratory Animal Research, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA., Cumming JN; Department of Discovery Chemistry, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Jan 15; Vol. 56, pp. 128463. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1016/j.bmcl.2021.128463
Abstrakt: This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed.
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Databáze: MEDLINE
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