Discovery of Potent, Selective, and State-Dependent Na_V1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure–Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides

Abstract

Voltage-gated sodium channel Na V 1.7 is a genetically validated target for pain. Identification of Na V 1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure−activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and statedependent Na V 1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over Na V 1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Inhibition of NaV1.7: the possibility of ideal analgesics

“…The unbound plasma concentration of 18 at the end of the formalin study at 3 mg kg −1 was 0.343 μM, which is 10-fold higher than the mNa V 1.7 IC 50 . 80…”

“…Therefore, many pharmaceutical companies have used mice in preclinical pharmacodynamic studies of sulphonamides and acyl sulphonamides. 48,77,78,80–89,91–94,99–101 Lilly and their collaborators reported the antitussive effects of compound 801, a sulphonamide-based Na V 1.7 inhibitor, on citric acid-evoked coughing in guinea pigs. 108,109 Recently, Merck reported a battery of four translational assays using rhesus monkeys: 1) microneurography for the action potential propagation in unmyelinated afferents, 2) threshold tracking for the excitability of myelinated afferents, 3) heat nociception test using clinical thermode device and 4) functional magnetic resonance imaging (fMRI) for olfactory function.…”

A magnetic porous organic polymer: catalytic application in the synthesis of hybrid pyridines with indole, triazole and sulfonamide moieties

“…Sulfonamides have been introduced as the major family of organosulfur compounds. 33–36 Therefore, these compounds with exceptional advantages including high stability, three-dimensional shape, hydrophilic properties, favorable physicochemical properties and having incomparable potential in modern antibiotics have revolutionized the areas of medicinal chemistry. 36,37 Sulfonamide families have special antibacterial properties and were introduced as highly important antimicrobials.…”