Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists.
Screening of library compounds has yielded pyrazolodiazepine derivatives with P2X7 receptor antagonist activity. To explore the structure-activity relationships (SAR) of these pyrazolodiazepines as human P2X7 receptor antagonists, derivatives were synthesized by substitutions at positions R2 and R3 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 P2X7 receptors. Moreover, the effect of these derivatives was assessed by measuring their effect on IL-1beta 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 R2 had fivefold greater activity than the derivative with a 5-isoquinolinyl at R2. Moreover, a benzyl moiety at R3 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 R1, a 3-methyl indole at R2, and a benzyl at R3, exhibited activity similar to that of the positive control, KN-62, as shown by the inhibitory effects of IL-1beta release.
Research Center for Biomolecular Nanotechnology, Department of Life Science, Gwangju Institute of Science & Technology, Gwangju, Republic of Korea.
Ju-Yeon
JY
Lee
Juan
J
Yu
Won Je
WJ
Cho
Hyojin
H
Ko
Yong-Chul
YC
Kim
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004996:Ethidium / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D004996:Ethidium