Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation.

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Claramunt RM, Lopez C, Perez-Medina C, Perez-Torralba M, Elguero J, Escames G, Acuna-Castroviejo D

Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation.

Bioorg Med Chem. 2009 Sep 1;17(17):6180-7. doi: 10.1016/j.bmc.2009.07.067. Epub 2009 Aug 6.

PubMed ID
19679481 [ View in PubMed
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Abstract

In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4-8), the second to the N-methyl derivatives (9-12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13-17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-Bromo-7-NitroindazoleNitric oxide synthase, brainIC 50 (nM)170N/AN/ADetails
3-Bromo-7-NitroindazoleNitric oxide synthase, inducibleIC 50 (nM)290N/AN/ADetails
7-NitroindazoleNitric oxide synthase, inducibleIC 50 (nM)5800N/AN/ADetails