Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNa_V1.7 Inhibitors for the Treatment of Pain

Abstract

The sodium channel Na1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na1.7, with high selectivity over the cardiac isoform Na1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective Na1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7

“…First-generation sulfonamide inhibitors are largely sequestered by plasma proteins (≥99% plasma protein bound). Standard equilibrium dialysis methods of determining plasma protein binding are known to underestimate binding in such instances, possibly explaining the need for high unbound exposures . Merck has explored multiple series of aryl sulfonamides bearing basic amine functional groups with an emphasis on improving ligand efficiency and lipophilic ligand efficiency. , Compound 6 exhibits an unbound fraction ( f u ) of 0.065 in mouse and was efficacious by subcutaneous (sc) administration in a formalin model at an unbound concentration of 1.5 μM, ∼50× the mNa V 1.7 IC 50 ; however, oral bioavailability was low ( F = 2%, 10 mpk in rat) .…”

Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core

“…Similar hydrophobic fragments also exist in the inhibitor GNE-131 and compound 1d (Fig. 1 ) [ 19 , 20 ]. In addition, compound 10o also has an alkaline tetrahydropyrrole side chain, which is similar to the ethylazetidine group in GX-936.…”

“…As a promising analgesic target, many Nav1.7 channel-selective inhibitors have been identified, such as GX-936, PF-05089771, AM-0466, and GNE-131 (Fig. 1 ) [ 17 , 19 , 23 , 37 ]. Among them, PF-05089771, a highly selective and potent Nav1.7 inhibitor, showed good effects on IEM patients and was used in clinical studies to treat painful diabetic peripheral neuropathy; however, the study was terminated in clinical phase II because PF-05089771 failed to achieve the therapeutic effect [ 37 ].…”

“…Among those compounds, GNE-131 (1c), with an innovative acyl group replacing a triazole group and a large hydrophobic adamantyl group as its side chain, showed good in vivo efficacy [ 19 ]. Based on that design, compound 1d has a simplified adamantane moiety instead of an adamantyl group and maintains good activity while displaying increased liver microsomal stability and improved efficacy (Fig.…”

Antibodies and venom peptides: new modalities for ion channels

“…1B), recently failed in patients suffering from painful diabetic neuropathy 34 , which led Pfizer to stop further development activities. Bankar et al suggested this failure possibly reflected insufficient Na V 1.7 targeting in the clinical study and recommend the evaluation of acyl-sulfonamides with better physiochemical and pharmacological properties 35 , including a longer residence time on the target 36 . Since PF-05089771 is intentionally peripherally restricted, compounds with improved blood brain barrier (BBB) penetrability in humans, might better engage NaV1.7 channels expressed close to or on the bouton of dorsal root ganglion (DRG) neuron dorsal horn synapse.…”