Significance TRPA1 channels are expressed primarily in sensory neurons with human genetic linkage to pain disorders. Despite the strong confidence for TRPA1 as a therapeutic target, few modulators have advanced to the clinic being hindered by poor physiochemical properties and narrow structure-activity relationships related to their site of interaction. We report the discovery of a potent and selective thiadiazole small molecule class of TRPA1 inhibitor that interacts with the N-terminal ankyrin repeat (ankyrinR) domain. The discovery of this interaction site provides opportunities to broaden TRPA1 small molecule drug discovery for the treatment of pain and adds insight into TRPA1 channel gating mechanisms.