REVISTA

Indazoles sustituidos como bloqueadores de Nav1.7 para el Tratamiento del Dolor.

Valoración Valoración: 3 Estrellas

Descripción: Artículo sobre el desarrollo de medicamentos bloqueantes de los canales iónicos dependientes de sodio en el tratamiento del dolor por osteortritis en ratas.

TITULO FUENTE ORIGINAL:

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain.

AUTORES:

Frost JM, DeGoey DA, Shi L, Gum RJ, Fricano MM, Lundgaard GL, El-Kouhen OF, Hsieh GC, Neelands T, Matulenko MA, Daanen JF, Pai M, Ghoreishi-Haack N, Zhan C, Zhang XF, Kort ME

REVISTA ABREV.:

J Med Chem

AÑO:

2016

REFERENCIA:

59(7):3373-9

DOI:

10.1021/acs.jmedchem.6b00063

RESUMEN ORIGINAL:

The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike... + Leer más

The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.

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