Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.

Autor: Smith GF; AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: Graham.smith@astrazeneca.com., Altman MD; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Andresen B; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Baker J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Brubaker JD; Blueprint Medicines, 38 Sidney St Suite 200, Cambridge, MA 02139, United States., Chen H; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Chen Y; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Childers M; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Donofrio A; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Ferguson H; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Fischer C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Fischmann TO; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Gibeau C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Hicks A; Oncorus, 50 Hampshire St. Suite 401, Cambridge, MA 02139, United States., Jin S; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Kattar S; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Kleinschek MA; Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, United States., Leccese E; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Lesburg C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Li C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Lim J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States. Electronic address: jongwon_lim@merck.com., Liu D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Maclean JKF; Redx Pharma, Block 33, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom., Mansoor F; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Moy LY; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Mulrooney EF; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Necheva AS; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Presland J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Rakhilina L; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Yang R; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Torres L; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Zhang-Hoover J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States., Northrup A; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Jun 15; Vol. 27 (12), pp. 2721-2726. Date of Electronic Publication: 2017 Apr 18.
DOI: 10.1016/j.bmcl.2017.04.050
Abstrakt: Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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