期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 21, 页码 6053-6058出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.09.053
关键词
IL-1 beta; Privileged structure; Pyrazolodiazepine; P2X7 Receptor
资金
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2009-0074289]
- institute of Medical System Engineering (iMSE) in the GIST, Korea
- National Research Foundation of Korea [2009-0074289] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Screening of library compounds has yielded pyrazolodiazepine derivatives with P2X(7) receptor antagonist activity. To explore the structure -activity relationships (SAR) of these pyrazolodiazepines as human P2X(7) receptor antagonists, derivatives were synthesized by substitutions at positions R-2 and R-3 of the pyrazolodiazepine skeleton. Using a 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP)-induced fluorescent ethidium uptake assay, the activities of these derivatives were tested in HEK-293 cells stably expressing human P2X(7) receptors. Moreover, the effect of these derivatives was assessed by measuring their effect on IL-1 beta release induced by BzATP-induced activation of differentiated THP-1 cells. A 2-phenethyl pyrazolodiazepine derivative with a 1-methyl-1H-3-indolyl group at position R-2 had fivefold greater activity than the derivative with a 5-isoquinolinyl at R-2. Moreover, a benzyl moiety at R-3 had fivefold greater activity than a bicyclic moiety. The stereochemical effect at C-6 showed a preference for the (R)-isomer. Among the series of active derivatives, compound 23b, with a phenethyl group at R-1, a 3-methyl indole at R-2, and a benzyl at R-3, exhibited activity similar to that of the positive control, KN-62, as shown by the inhibitory effects of IL-1 beta release. (C) 2009 Elsevier Ltd. All rights reserved.
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