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Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (Na V ) 1.7 with Potent Analgesic Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Jan 24; Vol. 62 (2), pp. 908-927. Date of Electronic Publication: 2018 Dec 21. - Publication Year :
- 2019
-
Abstract
- Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na <subscript>V</subscript> 1.7 inhibitors that are selective for Na <subscript>V</subscript> 1.7 over Na <subscript>V</subscript> 1.5 and highly efficacious in in vivo models of pain and hNa <subscript>V</subscript> 1.7 target engagement. An analysis of the physicochemical properties of literature Na <subscript>V</subscript> 1.7 inhibitors suggested that acyl sulfonamides with high f <subscript>sp3</subscript> could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against Na <subscript>V</subscript> 1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNa <subscript>V</subscript> 1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the Na <subscript>V</subscript> 1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious Na <subscript>V</subscript> 1.7 inhibitors reported to date.
- Subjects :
- Analgesics metabolism
Analgesics therapeutic use
Animals
Binding Sites
Drug Design
Half-Life
Humans
Male
Mice
Mice, Transgenic
Microsomes, Liver metabolism
Molecular Docking Simulation
NAV1.7 Voltage-Gated Sodium Channel metabolism
Pain chemically induced
Pain drug therapy
Pain pathology
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides metabolism
Sulfonamides therapeutic use
Voltage-Gated Sodium Channel Blockers metabolism
Voltage-Gated Sodium Channel Blockers therapeutic use
Analgesics chemistry
NAV1.7 Voltage-Gated Sodium Channel chemistry
Sulfonamides chemistry
Voltage-Gated Sodium Channel Blockers chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30499663
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b01621