Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship.

Istvan Macsari, Lars Sandberg, Yevgeni Besidski, Ylva Gravenfors, Tobias Ginman, Johan Bylund, Tjerk Bueters, Anders B Eriksson, Per-Eric Lund, Elisabet Venyike, Per I Arvidsson

Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. istvan.macsari@astrazeneca.com

Bioorganic & medicinal chemistry letters 2011 Jul 1

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Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Istvan Macsari, Lars Sandberg, Yevgeni Besidski, Ylva Gravenfors, Tobias Ginman, Johan Bylund, Tjerk Bueters, Anders B Eriksson, Per-Eric Lund, Elisabet Venyike, Per I Arvidsson. Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship. Bioorganic & medicinal chemistry letters. 2011 Jul 1;21(13):3871-6