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Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
- Source :
- Journal of Medicinal Chemistry. 60:5990-6017
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (i...
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
Bicyclic molecule
CYP3A4
Stereochemistry
Chemistry
Sodium channel
Sulfonamide
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
In vivo
Drug Discovery
Molecular Medicine
Structure–activity relationship
Selectivity
CYP2C9
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........bb6062704d531ce83c1a6122ecc44600