[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitlePreclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318.
Journal, issue, pagesPain, Vol. 166, Issue 8, Page 1893-1908, Year 2025
Publish dateApr 18, 2025
AuthorsLisa M Broad / Jeffrey G Suico / P Kellie Turner / Si Nie / Kirk W Johnson / Helen E Sanger / Lindsay A Wegiel / David C Sperry / David Remick / Magdalene Moran / Sam Malekiani / Donato Del Camino / Xinyuan Wu / Jayhong A Chong / Nathaniel T Blair / August V Wilke /
PubMed AbstractThe transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging ...The transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging to develop TRPA1 antagonists with appropriate properties to advance into clinical development. Herein, we describe the preclinical characterization and early clinical development of LY3526318, a potent, selective, and orally bioavailable TRPA1 antagonist. In vitro studies showed that LY3526318 reversibly inhibited recombinant TRPA1 channels with nanomolar potency that was conserved across species. LY3526318 also inhibited the function of native human and rat TRPA1 channels, including nociceptive dorsal root ganglion neuronal TRPA1 channels. In vivo studies showed that LY3526318 blocked formalin-evoked flinching behaviors and chronic Freund adjuvant-induced cold hypersensitivity in rats. Only male rats were used in these studies. Initial phase 1, single- and multiple-ascending dose studies evaluating pharmacokinetic and safety parameters of LY3526318 revealed a suboptimal pharmacokinetic profile leading to the development and study of a spray-dried dispersion (SDD) formulation of LY3526318. When dosed once daily at 250 mg, LY3526318-SDD showed a t max of 4 hours and t 1/2 of 12 hours, maintaining plasma exposures demonstrated to engage the TRPA1 target. Adverse events were transient and mild across all phase 1 studies. In summary, LY3526318 blocked TRPA1 in vitro and in vivo, inhibited behavioral signs of enhanced nociception in animal models, and was safe and well tolerated in phase 1 clinical studies, with LY3526318-SDD displaying an appropriate pharmacokinetic profile to advance to proof-of-concept studies in patients with chronic pain.
External linksPain / PubMed:40258136
MethodsEM (single particle)
Resolution2.7 Å
Structure data

48457

9moe

EMDB-48457, PDB-9moe:
Preclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

PDB-1bno:
NMR SOLUTION STRUCTURE OF THE N-TERMINAL DOMAIN OF DNA POLYMERASE BETA, MINIMIZED AVERAGE STRUCTURE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Pain receptor / TrpA1 / ion channel / ligand gating

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more