Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Abstract

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.

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

“…10 Given the high level of validation, there have been significant efforts towards identifying selective Na v 1.7 blockers for the treatment of pain. [11][12][13][14][15][16] In addition to subtype selectivity, sodium channel blockers can bind preferentially to the inactivated state of the channel which is thought to be of particular importance in the hyperexcitable neurons present in chronic pain. 17,18 Identification of state dependent blockers that can target channels in different kinetic states and tissues could thus impart improved functional selectivity.…”

“…H NMR (300 MHz, Methanol-d 4 ) δ 7.60 (td, J = 7.6, 1.7 Hz, 1H), 7.50 -7.31 (m, Fluoro-1-(2-fluorophenyl)-1H-indazol-3-yloxy)ethyl)oxazolidin-2-one,(12).Step 1: To a solution of 5-fluoro-1-(2-fluorophenyl)-1H-indazol-3-ol (3, from synthesis of 4, step 2, 1.34 g, 5.43 mmol), 2-(3oxazolidine)ethanol (Frinton Labs, 0.633 mL, 5.98 mmol) and tri-N-buylphosphine(1.47 mL, 5.98 mmol) in toluene (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine(1.51 g, 5.98 mmol) portionwise over 5 min. The mixture was warmed to 80 ºC and was allowed to stir for 5 h. The mixture was allowed to cool to ambient temperature and was stirred for 16 h. The mixture was filtered throughCelite and the filtrate was concentrated under reduced pressure and purified via column chromatography (SiO 2 , 10% ethyl acetate/hexanes to 100% ethyl acetate to 9:1:0.1 ethyl acetate : methanol : triethylamine) to give 2-(2-(5-fluoro-1-(2-fluorophenyl)-1H-indazol-3-yloxy)ethylamino)ethanol, 11 (0.762 g, 2.286 mmol, 42% yield).…”

Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor

“…However, although several selective Nav1.7 inhibitors have been described in the literature101112, none have fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects1112 and clinical progress has been slow1314. While the absence of efficacy has discouraged many in the field, and led some to question the drugabililty of Nav1.7, one possible explanation is that the pharmacological tools utilized provided sub-optimal block of Nav1.7.…”

“…While the absence of efficacy has discouraged many in the field, and led some to question the drugabililty of Nav1.7, one possible explanation is that the pharmacological tools utilized provided sub-optimal block of Nav1.7. Indeed, all so-called selective small molecule Nav1.7 blockers described to date are only partially selective121516 and inhibition of sodium channel isoforms other than Nav1.7 may preclude evaluation of maximally effective Nav1.7 blocking doses in-vivo . Furthermore, all small molecule sodium channel blockers identified to date exhibit a mechanism of action involving state-dependence151617, preferentially binding to and stabilizing the inactivated state, thereby reducing the number of channels available to open during subsequent depolarizations.…”

A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain

“…The contribution of Na v 1.7 to initiation of action potentials is related not only to its own activation characteristics, but also to its ability to amplify generator potentials and promote activation of other sensory neuron VSNaCs such as Na v 1.8 (Dib-Hajj et al., 2007). Numerous studies, including studies of selective channel antagonists, have directly implicated Na v 1.7 and Na v 1.8 in the pathogenesis of pain syndromes (Okuse et al, 1997; Black et al, 2004; Coggeshall et al, 2004; Yeomans et al, 2005; Strickland et al, 2008; Jarvis et al, 2007; Focken et al, 2016). Futhermore, in humans, mutations in the gene that encodes Na v 1.7 are associated with known pain disorders (Cummins et al, 2004; Fertleman et al, 2006), and Na v 1.7 knockout mice fail to develop hyperalgesia in several inflammatory pain models (Nassar et al, 2004).…”