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.
The role of calcium release-activated
calcium (CRAC) channels is
well characterized and is of particular importance in T-cell function.
CRAC channels are involved in the pathogenesis of several autoimmune
diseases, making it an attractive therapeutic target for treating
inflammatory diseases, like rheumatoid arthritis (RA). A systematic
structure–activity relationship study with the goal of optimizing
lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity
and a remarkable pharmacokinetic profile. Further characterization
in in vivo RA models and subsequent histopathological evaluation of
tissues led to the identification of 36 as a clinical
candidate. Compound 36 displayed an excellent safety
profile and had a sufficient safety margin to qualify it for use in
human testing. Oral administration of 36 in Phase 1 clinical
study in healthy volunteers established favorable safety, tolerability,
and good target engagement as measured by levels of IL-2 and TNF-α.
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