TY - JOUR
T1 - Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS)
T2 - Synthesis and biological evaluation
AU - Claramunt, Rosa M.
AU - López, Concepción
AU - Pérez-Medina, Carlos
AU - Pérez-Torralba, Marta
AU - Elguero, José
AU - Escames, Germaine
AU - Acuña-Castroviejo, Darío
N1 - Funding Information:
This work has been partially supported by Grants CTQ2007-62113 and SAF2005-07991-C02-01 (Ministerio de Educación y Ciencia, Spain), PI08-1664 (Instituto de Salud Carlos III, Spain), and P07-CTS-03135 (Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain).
PY - 2009/9/1
Y1 - 2009/9/1
N2 - 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.
AB - 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.
KW - Fluorine pharmacophore
KW - Indazoles
KW - NOS-I
KW - NOS-II
UR - http://www.scopus.com/inward/record.url?scp=68649084717&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2009.07.067
DO - 10.1016/j.bmc.2009.07.067
M3 - Article
C2 - 19679481
AN - SCOPUS:68649084717
SN - 0968-0896
VL - 17
SP - 6180
EP - 6187
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 17
ER -