Discovery of Selective Inhibitors of NaV1.7 Templated on Saxitoxin as Therapeutics for Pain

The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal mu...

Full description

Saved in:
Bibliographic Details
Published inACS medicinal chemistry letters Vol. 13; no. 11; pp. 1763 - 1768
Main Authors Pajouhesh, Hassan, Delwig, Anton, Beckley, Jacob T., Klas, Sheri, Monteleone, Dennis, Zhou, Xiang, Luu, George, Du Bois, J., Hunter, John C., Mulcahy, John V.
Format Journal Article
LanguageEnglish
Published American Chemical Society 10.11.2022
Subjects
Online AccessGet full text

Cover

Loading…
Abstract The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of NaV1.7. Most inhibitors of NaV1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate NaV1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.
AbstractList The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of NaV1.7. Most inhibitors of NaV1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate NaV1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.
The voltage-gated sodium channel isoform Na V 1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of Na V 1.7. Most inhibitors of Na V 1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate Na V 1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25 , exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.
Author Beckley, Jacob T.
Klas, Sheri
Monteleone, Dennis
Hunter, John C.
Mulcahy, John V.
Zhou, Xiang
Delwig, Anton
Du Bois, J.
Luu, George
Pajouhesh, Hassan
AuthorAffiliation Department of Chemistry
Stanford University
SiteOne Therapeutics, Inc
AuthorAffiliation_xml – name: SiteOne Therapeutics, Inc
– name: Stanford University
– name: Department of Chemistry
Author_xml – sequence: 1
  givenname: Hassan
  surname: Pajouhesh
  fullname: Pajouhesh, Hassan
  organization: SiteOne Therapeutics, Inc
– sequence: 2
  givenname: Anton
  surname: Delwig
  fullname: Delwig, Anton
  organization: SiteOne Therapeutics, Inc
– sequence: 3
  givenname: Jacob T.
  surname: Beckley
  fullname: Beckley, Jacob T.
  organization: SiteOne Therapeutics, Inc
– sequence: 4
  givenname: Sheri
  surname: Klas
  fullname: Klas, Sheri
  organization: SiteOne Therapeutics, Inc
– sequence: 5
  givenname: Dennis
  orcidid: 0000-0001-9172-663X
  surname: Monteleone
  fullname: Monteleone, Dennis
  organization: SiteOne Therapeutics, Inc
– sequence: 6
  givenname: Xiang
  surname: Zhou
  fullname: Zhou, Xiang
  organization: SiteOne Therapeutics, Inc
– sequence: 7
  givenname: George
  surname: Luu
  fullname: Luu, George
  organization: SiteOne Therapeutics, Inc
– sequence: 8
  givenname: J.
  orcidid: 0000-0001-7847-1548
  surname: Du Bois
  fullname: Du Bois, J.
  organization: Stanford University
– sequence: 9
  givenname: John C.
  orcidid: 0000-0003-1426-0164
  surname: Hunter
  fullname: Hunter, John C.
  organization: SiteOne Therapeutics, Inc
– sequence: 10
  givenname: John V.
  orcidid: 0000-0002-3997-6073
  surname: Mulcahy
  fullname: Mulcahy, John V.
  email: john.mulcahy@site1therapeutics.com
  organization: SiteOne Therapeutics, Inc
BookMark eNpVUctOwzAQtBCIUuAXkI9cWuzYsZ0LEuJZqQIkChcOlpNsqFFiF9upyt-Tih7gtKOd0Wh3Zoz2nXeA0BklU0oyemGq2EFdLaFrIaVpVhHCpNpDR7TgapIrme__wSM0jvGTEFFISQ7RiAmm8oKJI_R-Y2Pl1xC-sW_wC7RQJbsGPHNLW9rkQ9zuH80bnUq8gG7VmgQ19g6_mM3Ab6zDJuLFEoJZQZ9sFXHjA3421p2gg8a0EU538xi93t0urh8m86f72fXVfGIyJdL2QGBSlnldQMYVzUquiOFlLYuGE6q45KQ2TQWibErBDC1yTokcEFQ1bxQ7Rpe_vqu-3IYCLgXT6lWwnQnf2hur_zPOLvWHX-tCCCoJHwzOdwbBf_UQk-6GVKBtjQPfR51JJrkQLM8HafYrHQrQn74PbvhMU6K3rej_rehdK-wHs6yGXg
ContentType Journal Article
Copyright 2022 American Chemical Society
2022 American Chemical Society 2022 American Chemical Society
Copyright_xml – notice: 2022 American Chemical Society
– notice: 2022 American Chemical Society 2022 American Chemical Society
DBID 7X8
5PM
DOI 10.1021/acsmedchemlett.2c00378
DatabaseName MEDLINE - Academic
PubMed Central (Full Participant titles)
DatabaseTitle MEDLINE - Academic
DatabaseTitleList MEDLINE - Academic


DeliveryMethod fulltext_linktorsrc
Discipline Pharmacy, Therapeutics, & Pharmacology
EISSN 1948-5875
EndPage 1768
ExternalDocumentID a839994374
GrantInformation_xml – fundername: ;
  grantid: R44NS081887
GroupedDBID ---
53G
55A
5VS
7~N
AABXI
ABFRP
ABMVS
ABQRX
ABUCX
ACGFO
ACGFS
ACS
ADBBV
ADHLV
AEESW
AENEX
AFEFF
AHGAQ
ALMA_UNASSIGNED_HOLDINGS
AOIJS
AQSVZ
BAWUL
DIK
EBS
ED~
F5P
GGK
GNL
GX1
IH9
JG~
OK1
P2P
RNS
ROL
RPM
UI2
VF5
VG9
W1F
XKZ
7X8
ABJNI
BAANH
CUPRZ
HYE
5PM
ID FETCH-LOGICAL-a286t-587e377b5d9e24812b480a4bd79f40184740dafce6bfb63a195410763aecd4f83
IEDL.DBID RPM
ISSN 1948-5875
IngestDate Tue Sep 17 21:29:27 EDT 2024
Fri Aug 16 21:37:31 EDT 2024
Sat Nov 12 03:46:24 EST 2022
IsDoiOpenAccess false
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 11
Keywords Nav1.7
non-opioid
pain
sodium channel
saxitoxin
Language English
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-a286t-587e377b5d9e24812b480a4bd79f40184740dafce6bfb63a195410763aecd4f83
Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ORCID 0000-0003-1426-0164
0000-0001-7847-1548
0000-0002-3997-6073
0000-0001-9172-663X
PMID 36385936
PQID 2737466355
PQPubID 23479
PageCount 6
ParticipantIDs pubmedcentral_primary_oai_pubmedcentral_nih_gov_9661704
proquest_miscellaneous_2737466355
acs_journals_10_1021_acsmedchemlett_2c00378
PublicationCentury 2000
PublicationDate 2022-11-10
PublicationDateYYYYMMDD 2022-11-10
PublicationDate_xml – month: 11
  year: 2022
  text: 2022-11-10
  day: 10
PublicationDecade 2020
PublicationTitle ACS medicinal chemistry letters
PublicationTitleAlternate ACS Med. Chem. Lett
PublicationYear 2022
Publisher American Chemical Society
Publisher_xml – name: American Chemical Society
SSID ssj0069770
Score 2.363117
Snippet The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity...
The voltage-gated sodium channel isoform Na V 1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain....
SourceID pubmedcentral
proquest
acs
SourceType Open Access Repository
Aggregation Database
Publisher
StartPage 1763
SubjectTerms Letter
SummonAdditionalLinks – databaseName: American Chemical Society Publications
  dbid: ACS
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1ZS-RAEC7UfdkXjz1wvOiFxZc1Y9Lp6U4exQN3YWWWGRdhH0KfTFB7xGTA8ddbnZnBDSLoW0iHJF191FdUfV8DfNc5DTjCRI5TGTFNdaQYRyBnYinRg7s0C2zk3xf8_JL9uupdLUH8SgafJodSV6FUcWRvsSN1l-ogmZItwwcqMAYPYOh4sNh7OaKZhgKZs8AnEr0FJ_jV9wSnpKsWvGwXR_7nbc7W4M-CszMrMrnuTmrV1Y8vJRzf3JF1WJ1DT3I0mysbsGT9J9jvz7Srpwdk-EzFqg7IPuk_q1pPP8O_k7LSod5zSsaODJrjc3CnJD_9qFRlOLMn3L-Qf5OuIEN7e3eDKNaQsScD-YDtD6Unsmp9hCBgJn1Z-i9weXY6PD6P5iczRJJmvA6mtakQqmdySxliBMWyWDJlRO4wYEOPx2IjnbZcOcVTGWTlMM7EK6sNc1n6FVb82NtNICk-mnGDyDJPGMafGTOB1-lSSx13PdqBH2i4Yr6yqqJJmtOkaFuzmFuzA98WA1ngOgnJD-nteFIVCNMEa-BVB0RrhIu7ma5HEZS22y2-HDWK2xgTJiJmW-_6l234SANXoqkZ3IGV-n5idxHB1GqvmbRP15fwlw
  priority: 102
  providerName: American Chemical Society
Title Discovery of Selective Inhibitors of NaV1.7 Templated on Saxitoxin as Therapeutics for Pain
URI http://dx.doi.org/10.1021/acsmedchemlett.2c00378
https://search.proquest.com/docview/2737466355
https://pubmed.ncbi.nlm.nih.gov/PMC9661704
Volume 13
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1LS8NAEF7UkxfxifXFCtKLpk02m016lPqGSqFVCh7CPmmg3RbTQvvvnU0TNFcvIWQTEmYnO9-w33yD0I3sEIcjlGcY4R6VRHqCMgByyuccIrgJE1eN3HtnLx_0bRSNtlBU1cIUpH0pspadTFs2GxfcyvlUtiueWLvf6wJED2KftrfRNoTfKkXfLL8MAI1flQKToM1l7piOYz0FOyxaRDrFFdelLwTPc-3sXFiSeQ1g1umRf-LN0z7aK4Eivt980AHa0vYQNfsbpen1HR7-Fk7ld7iJ-78a1Osj9PWQ5dKxM9d4ZvCgaHYD6xp-teNMZK7Djrv-zj-DVoyHejqfAOZUeGbxgK9gfJVZzPPaSzDAW9znmT1GH0-Pw-6LV_ZR8DhJ2MKLkliHcSwi1dGEQkQXNPE5FSruGEivID5RX3EjNRNGsJA7ETjICuFMS0VNEp6gHTuz-hThEG5NmAIc2AkoZIsJVa4K04SaGGYi0kC3YMy0_A_ytNjiJkFan4W0nIUGuq6MnoJXu60KbvVsmacAqmJagKEGimuzkc43Khyp08Wuj4C7FPrYpXuc_fvJc7RLXJVDwfa7QDuL76W-BOyxEFeAvbsDOD6PgqvC734ANmbfKQ
link.rule.ids 230,314,727,780,784,885,27076,27924,27925,53791,53793,56738,56788
linkProvider National Library of Medicine
linkToHtml http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3PT9swFLYYHLbLBGzTOmB40sRlpE0cx06OEz9UGK0qUSakHSz_VCNRtyJFov89z2kiliu3KHaU6PnF73vy976H0E9dkIAjTOQYkRHVREeKMgByJpYSIrhL81CNPBqz4R29vs_ut1DW1sLUpH2tyr5_mPd9Oau5lcu5HrQ8scFkdAYQPeExHbxDO1nKi6RN0jcbMANIE7fFwCQZSF0FruPMzsESqz7RQXMl9OlLwfdCQ7sQmHTVgZhdguR_EedyF31soCL-vfmkPbRl_T46mWy0ptenePpaOlWd4hM8eVWhXn9C_87LSgd-5hovHL6t293Azoav_KxUZeixE-6P5d-kz_HUzpcPgDoNXnh8K59h_Ln0WFadl2AAuHgiS_8Z3V1eTM-GUdNJIZIkZ6soy7lNOVeZKSyhENMVzWNJleGFgwQLIhSNjXTaMuUUS2WQgYO8EK6sNtTl6Re07RfefkU4hak5M4AEi4RCvphTE-owXWqJYy4jPfQLjCmaP6ES9SE3SUR3FUSzCj30ozW6AL8OhxXS28VTJQBWcVrDoR7indUQy40OhwjK2N0RcJhaIbtxkG9vfvIYvR9ORzfi5mr85wB9IKHmoeb-HaLt1eOTPQIkslLfa797AZco4JU
linkToPdf http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3fS-QwEA7-APFFvFNxPfVyIL5ot22apt1H0Vv01KXgKoIPIT_Zgptdriu4_72Tbhftq2-lSWmZTDPfkG--QehE9YjHETqwjIiAKqICSRkAOR0JARHcJrmvRr4fsOtH-u85ff7S6qsm7StZdt3ruOvKUc2tnI5VuOSJhcX9JUD0OItoONU2XEXraQJOtkzUF5swA1gTLQuCSRwKVXm-48iMwRqzLlFed8X36kvA_3xTOx-cVNWCmW2S5Jeo099GWw1cxBeLz_qBVoz7iU6Lhd70_BwPP8unqnN8iotPJer5Dnq5KivlOZpzPLH4oW55A7sbvnGjUpa-z46_PxBPcTfDQzOevgLy1Hji8IN4h_H30mFRtV6CAeTiQpRuFz32_w4vr4Omm0IgSM5mQZpnJskymeqeIRTiuqR5JKjUWc9CkgVRikZaWGWYtJIlwkvBQW4IV0ZpavNkD625iTP7CCcwNWca0GAvppAz5lT7WkybGGKZTUkHnYExefM3VLw-6CYxb68Cb1ahg_4sjc7Bt_2BhXBm8lZxgFYZrSFRB2Wt1eDThRYH9-rY7RFwmlolu3GSg28_-RttFFd9fnczuP2FNokve6jpf4dobfb_zRwBGJnJ49rtPgDNEeGo
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Discovery+of+Selective+Inhibitors+of+NaV1.7+Templated+on+Saxitoxin+as+Therapeutics+for+Pain&rft.jtitle=ACS+medicinal+chemistry+letters&rft.au=Pajouhesh%2C+Hassan&rft.au=Delwig%2C+Anton&rft.au=Beckley%2C+Jacob+T&rft.au=Klas%2C+Sheri&rft.date=2022-11-10&rft.issn=1948-5875&rft.eissn=1948-5875&rft.volume=13&rft.issue=11&rft.spage=1763&rft.epage=1768&rft_id=info:doi/10.1021%2Facsmedchemlett.2c00378&rft.externalDBID=NO_FULL_TEXT
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1948-5875&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1948-5875&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1948-5875&client=summon