TRPV4: A Promising Therapeutic Target Ion Channel─Discovery of Ultrapotent Selective Antagonists

  • J Med Chem. 2026 Jul 23;69(14):16926-16948. doi: 10.1021/acs.jmedchem.6c00672.
Magnus Nilsson  1 ,  Sara J Bonvini  2 ,  Emelyne Diers  1 ,  Julia Johansson  3 ,  Nina Lawrence  4 ,  Henrik Andersson  5 ,  Stefan von Berg  1 ,  Susanne Berglund  1 ,  Mark Birrell  2 ,  Peter Bold  4 ,  Matthew Bridgland-Taylor  6 ,  Elisabeth Bäck  7 ,  Karin E Carlsson  8 ,  Samy Chammaa Tortola  1 ,  Werngard Czechtizky  1 ,  Ian L Dale  9 ,  Said El-Haou  9 ,  Huanxi Feng  10 ,  Peter R Hansen  1 ,  Eva L Hansson  5 ,  Ramon Hendrickx  4 ,  Thomas Hochdörfer  5 ,  Glyn Hughes  1 ,  Marie H Larsson  11 ,  Richard J Lewis  1 ,  Gareth Maglennon  12 ,  Mickael Mogemark  3 ,  Ziyang Nan  10 ,  Rikard Pehrson  4 ,  Tristan D Reuillon  1 ,  Christian Tyrchan  1 ,  Inmaculada C Villar  6 ,  Guido Zagnoli-Vieira  13 ,  Wenzhen Yang  10 ,  Hongtao Zhao  1
Affiliations
  • 1. Medicinal Chemistry, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 2. In Vivo Bioscience, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, London SW7 2AZ, United Kingdom.
  • 3. Safety Sciences, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 4. DMPK, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 5. Discovery Sciences, Research and Early Development, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 6. Safety Sciences, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
  • 7. Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 8. Global Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 9. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
  • 10. Pharmaron Beijing Co., Ltd., Taihe Road BDA, Beijing 100176, P. R. China.
  • 11. Projects, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 12. Pathology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
  • 13. Assays, Profiling & Cell Sciences, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
PMID: 42434955 DOI: 10.1021/acs.jmedchem.6c00672
Abstract

TRPV4 is a polymodal, calcium-permeable channel broadly expressed and enriched in epithelia, where it integrates mechanical, osmotic, and chemical cues to regulate calcium signaling. Although TRPV4 antagonism has long been pursued therapeutically, only one antagonist has reached patients and it lacked efficacy, likely due to pharmacokinetic limitations. We describe a novel series of small-molecule TRPV4 antagonist discovered via high-throughput screening and optimized for potency, selectivity, and developability. The lead, compound 39, demonstrates favorable absorption and elimination supporting a low, predicted once-daily oral dose, with robust margins to off-target pharmacology in early safety studies. In vivo, compound 39 attenuates responses in a mechanistically relevant cough model, indicating target engagement and functional efficacy. These findings position the preclinical compound 39 as a differentiated TRPV4 antagonist with drug-like pharmacokinetics and an encouraging nonclinical safety profile.

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