Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.

Autor: Winneroski LL; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Schiffler MA; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Erickson JA; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., May PC; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Monk SA; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Timm DE; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Audia JE; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Beck JP; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Boggs LN; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Borders AR; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Boyer RD; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Brier RA; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Hudziak KJ; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Klimkowski VJ; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Garcia Losada P; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Mathes BM; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Stout SL; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Watson BM; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA., Mergott DJ; Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: mergottdu@lilly.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Jul 01; Vol. 23 (13), pp. 3260-8. Date of Electronic Publication: 2015 May 06.
DOI: 10.1016/j.bmc.2015.04.062
Abstrakt: The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.
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Databáze: MEDLINE
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