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

doi:10.1016/j.bmcl.2011.05.041

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

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3871-6. doi: 10.1016/j.bmcl.2011.05.041. Epub 2011 May 18.

Authors

Istvan Macsari¹, Lars Sandberg, Yevgeni Besidski, Ylva Gravenfors, Tobias Ginman, Johan Bylund, Tjerk Bueters, Anders B Eriksson, Per-Eric Lund, Elisabet Venyike, Per I Arvidsson

Affiliation

¹ Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. istvan.macsari@astrazeneca.com

PMID: 21641215
DOI: 10.1016/j.bmcl.2011.05.041

Abstract

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.

MeSH terms

Administration, Oral
Animals
Carbamates / administration & dosage
Carbamates / chemistry*
Carbamates / therapeutic use
Humans
Infusion Pumps
Inhibitory Concentration 50
Isoxazoles / administration & dosage
Isoxazoles / chemistry*
Isoxazoles / pharmacology*
Isoxazoles / therapeutic use
Molecular Structure
Pain / drug therapy
Rats
Sodium Channel Blockers / administration & dosage
Sodium Channel Blockers / chemistry*
Sodium Channel Blockers / pharmacology*
Structure-Activity Relationship

Substances

Carbamates
Isoxazoles
Sodium Channel Blockers