Abstract
Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.
MeSH terms
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Animals
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Cell Line
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Cytochrome P-450 CYP3A / biosynthesis
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Cytochrome P-450 CYP3A Inhibitors / chemistry
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Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
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Cytochrome P-450 CYP3A Inhibitors / pharmacology
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Dogs
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Enzyme Induction
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Histamine
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Humans
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Isoquinolines / administration & dosage
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Isoquinolines / chemistry*
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Isoquinolines / pharmacokinetics
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Male
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Mice, Inbred C57BL
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NAV1.7 Voltage-Gated Sodium Channel / metabolism*
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Pregnane X Receptor
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Pruritus / chemically induced
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Pruritus / prevention & control
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Rats
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Receptors, Steroid / agonists
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Structure-Activity Relationship
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Sulfonamides / administration & dosage
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Voltage-Gated Sodium Channel Blockers / chemistry*
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Voltage-Gated Sodium Channel Blockers / pharmacokinetics
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Voltage-Gated Sodium Channel Blockers / pharmacology
Substances
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1-(2-fluoro-5-methoxy-3'-(trifluoromethyl)-(1,1'-biphenyl)-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide
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Cytochrome P-450 CYP3A Inhibitors
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Isoquinolines
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NAV1.7 Voltage-Gated Sodium Channel
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Pregnane X Receptor
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Receptors, Steroid
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Sulfonamides
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Voltage-Gated Sodium Channel Blockers
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Histamine
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Cytochrome P-450 CYP3A