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 Cregion
were synthesized to understand the binding site characteristics of TRPV1 receptors.
Methods: 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.