Structure and activity relationship in the

Bioorg. Med. Chem. Lett. · Sep 2012

Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers.

Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.

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- Inger Kers, Gabor Csjernyik, Istvan Macsari, Martin Nylöf, Lars Sandberg, Karin Skogholm, Tjerk Bueters, Anders B Eriksson, Sandra Oerther, Per-Eric Lund, Elisabet Venyike, Jan-Erik Nyström, and Yevgeni Besidski.
- Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. inger.kers@telia.com
- Bioorg. Med. Chem. Lett. 2012 Sep 1;22(17):5618-24.
AbstractRecent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.Copyright © 2012 Elsevier Ltd. All rights reserved.

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Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers.

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