Discovery of Arylsulfonamide Na_v1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile

Abstract

The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro–in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.

Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve

“…All compound potencies were measured in a hyperpolarized protocol as described in the methods. Prior experiments had determined that the hyperpolarized potency of compounds on NaV1.7 was a good predictor of their in vivo analgesic efficacy across several different preclinical animal models – the in vitro IC 50 was predictive of the in vivo IC 90 [ 23 ]. The calculated IC 50 values for five compounds ( SSCI-1 , 3 – 6, Figure 1 ) are reported in Table 1 .…”

Inhibition of NaV1.7: the possibility of ideal analgesics

“…Based on these results, the estimated human dose varies from 40 (BID) to 4600 mg (BID), and they concluded that further optimisation was needed to acquire clinical candidates. 91…”

“…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.…”

“…Based on these results, the estimated human dose varies from 40 (BID) to 4600 mg (BID), and they concluded that further optimisation was needed to acquire clinical candidates. 91 Bristol-Myers Squibb reported the identification of compound 31. In their article, both compounds 24 and 31 were assessed for their ability to reduce nociceptive behaviour in a formalin test in mice, revealing that 24 was effective at 60 mg kg −1 whereas 31 was not effective at 100 mg kg −1 .…”

“…In fact, compound 30 reported by Merck inhibited Na V 1.7 in a conformation close to the resting state and demonstrated potent in vivo efficacy at extremely low Na V 1.7 coverage (0.04-fold). 91 Janssen reported a close relationship between the Na V 1.7 resting state and pharmacological insensitivity to pain through the identification of the peptide JNJ63955918. 122 Both cases may approximate the pathological condition observed in patients with CIP.…”