Dataset Information

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

ABSTRACT: The voltage-gated sodium channel Na_v1.7 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 Na_v1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Na_v1.6 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 Na_v1.7 inhibitors to afford improved selectivity over Na_v1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Na_v1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Na_v1.7, selectivity over Na_v1.5 and Na_v1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.

SUBMITTER: Roecker AJ

PROVIDER: S-EPMC8201757 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of Arylsulfonamide Nav1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

Roecker Anthony J AJ Layton Mark E ME Pero Joseph E JE Kelly Michael J MJ Greshock Thomas J TJ Kraus Richard L RL Li Yuxing Y Klein Rebecca R Clements Michelle M Daley Christopher C Jovanovska Aneta A Ballard Jeanine E JE Wang Deping D Zhao Fuqiang F Brunskill Andrew P J APJ Peng Xuanjia X Wang Xiu X Sun Haiyan H Houghton Andrea K AK Burgey Christopher S CS

ACS medicinal chemistry letters 20210601 6

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 ...[more]

PMID: 34141090

Similar Datasets

Project description:Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically-validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the NaV1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) NaV1.7/NaV1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na+ currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E4K was significantly improved for hNaV1.6, leading to a decreased hNaV1.7/hNaV1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E1G/E4G and HwTx-IV E4K/R26Q). In contrast, increased selectivity ratios (>46) were obtained if the E4K mutation was combined to an additional double substitution (R 26A/Y33W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNaV1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNaV1.6 and/or hNaV1.7 subtypes. In addition, selective analogues for hNaV1.7, possessing better safety profiles, were produced to limit neuromuscular impairments.

Dataset Information

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

Publications

Discovery of Arylsulfonamide Na<sub>v</sub>1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets