Design, synthesis, and evaluation of isoquinoline ureas as trpv1 antagonists

Nehaben A. Gujarati, Bradley J. Undem, Vijaya L. Korlipara

Research output: Contribution to journalArticlepeer-review


Background: The inhibition of transient receptor potential vanilloid receptor 1 (TRPV1) has emerged as a novel approach for the treatment of various pain states. Pyrrolidinyl urea, SB 705498 with pKb = 7.3 in guinea pig TRPV1 receptor has been investigated in Phase II clinical trials for pain and chronic cough. Another heteroaryl urea derivative, A-425619 1, has been reported to be a potent and selective TRPV1 antagonist of capsaicin-evoked receptor activation with an IC50 value of 4 nM in hTRPV1. Objective: A series of thirteen A-425619 1 analogues with modifications centered around the C-region were synthesized to understand the binding site characteristics of TRPV1 receptors. Method: We synthesized a series of isoquinoline ureas and evaluated their antagonist potency using smooth muscle assay using guinea pig trachea along with the evaluation of the molecular properties and molecular modeling using CoMFA studies. Results: p-Chloro 4, p-bromo 5, m-isothiocyanate 15, and p-isothiocyanate 16 derivatives were found to be the most potent members of the series with pKb values in the range of 7.3-7.4 in the functional assay using guinea pig trachea. The lead compound A-425619 1 exhibited a pKb value of 8.1 in this assay. Conclusion: The para-substituted analogues were found to be more potent than the ortho-and meta-analogues in the biological assay. This observation was further supported by molecular modeling studies using CoMFA.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalMedicinal Chemistry
Issue number2
StatePublished - 2020


  • A-425619
  • Isoquinoline ureas
  • Pain
  • SB 705498
  • Smooth Muscle Assay
  • TRPV1

ASJC Scopus subject areas

  • Drug Discovery


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