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  2. 3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models

3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models

  • J Med Chem. 2012 Aug 9;55(15):6866-80. doi: 10.1021/jm300623u.
Istvan Macsari 1 Yevgeni Besidski Gabor Csjernyik Linda I Nilsson Lars Sandberg Ulrika Yngve Kristofer Ahlin Tjerk Bueters Anders B Eriksson Per-Eric Lund Elisabet Venyike Sandra Oerther Karin Hygge Blakeman Lei Luo Per I Arvidsson
Affiliations

Affiliation

  • 1 Medicinal Chemistry, CNSP iMed, AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden. istvan.macsari@astrazeneca.com
Abstract

The voltage-gated Sodium Channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective Sodium Channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

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