Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly(ADP-ribose) polymerase-1 inhibitors.

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Zhang WT, Ruan JL, Wu PF, Jiang FC, Zhang LN, Fang W, Chen XL, Wang Y, Cao BS, Chen GY, Zhu YJ, Gu J, Chen JG

Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly(ADP-ribose) polymerase-1 inhibitors.

J Med Chem. 2009 Feb 12;52(3):718-25. doi: 10.1021/jm800902t.

PubMed ID

19125579 [ View in PubMed

]

Abstract

A series of novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors were designed within 2-aminothiazole analogues (4-10) based on a constructed three-dimensional pharmacophore model. After synthesis, the inhibitory effect on PARP-1 activity and the cytoprotective action of these compounds were tested and evaluated. Among them, compounds 4-6 and 10 appeared to be potent PARP-1 inhibitors with IC(50) values less than 1 microM, which had been perfectly predicted by pharmacophore model. These compounds proved to be highly potent against cell injury induced by H(2)O(2) and oxygen-glucose deprivation (OGD) in PC12 cells. These novel 2-aminothiazole analogues are potentially applicable as neuroprotective agents for the treatment of neurological diseases.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-{3-[4-(4-Fluorophenyl)-3,6-Dihydro-1(2h)-Pyridinyl]Propyl}-8-Methyl-4(3h)-Quinazolinone	Poly [ADP-ribose] polymerase 1	IC 50 (nM)	16	N/A	N/A	Details