Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.

2,4(5)-Diarylimidazoles as Inhibitors of hNaV1.2 Sodium Channels: Pharmacological Evaluationand Structure-Property Relationships / Fantini, M.; Rivara, Mirko; Zuliani, Valentina; Kalmar, C. L.; Vacondio, Federica; Silva, Claudia; Baheti, A. R.; Singh, N.; Merrick, E. C.; Katari, R. S.; Cocconcelli, G.; Ghiron, C.; Patel, M. K.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 17:(2009), pp. 3642-3648. [10.1016/j.bmc.2009.03.067]

2,4(5)-Diarylimidazoles as Inhibitors of hNaV1.2 Sodium Channels: Pharmacological Evaluationand Structure-Property Relationships

RIVARA, Mirko;ZULIANI, Valentina;VACONDIO, Federica;SILVA, Claudia;
2009-01-01

Abstract

Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.
2009
2,4(5)-Diarylimidazoles as Inhibitors of hNaV1.2 Sodium Channels: Pharmacological Evaluationand Structure-Property Relationships / Fantini, M.; Rivara, Mirko; Zuliani, Valentina; Kalmar, C. L.; Vacondio, Federica; Silva, Claudia; Baheti, A. R.; Singh, N.; Merrick, E. C.; Katari, R. S.; Cocconcelli, G.; Ghiron, C.; Patel, M. K.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 17:(2009), pp. 3642-3648. [10.1016/j.bmc.2009.03.067]
File in questo prodotto:
File Dimensione Formato  
abstract_bmc_2009.pdf

non disponibili

Tipologia: Abstract
Licenza: Creative commons
Dimensione 9.02 kB
Formato Adobe PDF
9.02 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
bmc_2009.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 473.08 kB
Formato Adobe PDF
473.08 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2293375
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 29
  • ???jsp.display-item.citation.isi??? 31
social impact