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Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform Na V 1.7.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Oct 10; Vol. 62 (19), pp. 8695-8710. Date of Electronic Publication: 2019 May 07. - Publication Year :
- 2019
-
Abstract
- Voltage-gated sodium ion channel subtype 1.7 (Na <subscript>V</subscript> 1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional Na <subscript>V</subscript> 1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na <superscript>+</superscript> ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism around the potential of selective Na <subscript>V</subscript> 1.7 inhibitors as human therapeutics. In this Perspective, we discuss the attributes and limitations of recently disclosed investigational drugs targeting Na <subscript>V</subscript> 1.7 and review evidence that, by better understanding the requirements for selectivity and target engagement, the opportunity to deliver effective analgesic medicines targeting Na <subscript>V</subscript> 1.7 endures.
- Subjects :
- Analgesics metabolism
Analgesics pharmacology
Analgesics therapeutic use
Animals
Disease Models, Animal
Humans
NAV1.7 Voltage-Gated Sodium Channel chemistry
Pain drug therapy
Pain pathology
Protein Isoforms antagonists & inhibitors
Protein Isoforms metabolism
Signal Transduction drug effects
Sodium Channel Blockers metabolism
Sodium Channel Blockers pharmacology
Sodium Channel Blockers therapeutic use
Sulfonamides chemistry
Sulfonamides metabolism
Analgesics chemistry
NAV1.7 Voltage-Gated Sodium Channel metabolism
Sodium Channel Blockers chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31012583
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b01906