ABSTRACT:We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNa V 1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNa V 1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of Na V 1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNa V 1.7 as a drug target for the treatment of pain. KEYWORDS: Sodium channel, Na V 1.7, Na V 1.5, pain, aryl sulfonamide, formalin model, cold allodynia T he sodium channel Na V 1.7 belongs to a family of transmembrane voltage gated sodium channels, which consists of nine isoforms in mammals (Na V 1.1 to Na V 1.9).1−4 Na V 1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Na V 1.7 and its encoding SCN9A gene to painful disorders in humans. Gain-of-function mutations in the SCN9A gene result in painful conditions such as inherited erythromelalgia, paroxysmal extreme pain disorder, and idiopathic small fiber neuropathies. In contrast, loss-of-function mutations in the SCN9A gene were found to be the genetic cause of a rare disorder called congenital insensitivity to pain, characterized by a complete loss of the ability to sense painful stimuli. It is noteworthy that no significant side effects have been reported in people lacking Na V 1.7, such as cognitive, motor, or non-nociceptive sensory impairments other than anosmia, giving further support to the concept of Na V 1.7 antagonists as analgesics.1−4 The predominant expression of the Na V 1.7 isoform in the PNS may offer a pathway to limit CNS-related adverse effects by developing compounds that do not cross the blood−brain barrier. Combined, these observations and findings have made Na V 1.7 a promising target for drug development for the treatment of pain. Indeed, there has been tremendous interest in the development of small molecule Na V 1.7 inhibitors as analgesics, particularly isoform-selective inhibitors, and coverage of the progress has been the subject of several excellent reviews. 1−7 In recent years, a series of aryl sulfonamides as Na V inhibitors have been reported that appear to be highly selective for Na V 1.7 over the cardiac ion channel Na V 1.5. [4][5][6]8 Since block of the Na V 1.5 channel may lead to arrhythmia and thus limit the therapeutic potential of nonselective Na V 1.7 inhibitors, isoform-selective inhibitors have attracted considerable interest due to their potential to avoid these adverse events.3,5 An example is aryl sulfonamide PF-04856264 ( Figure 1), which selectively blocks Na V 1.7 over Na V 1.5 and Na V 1.3.