Nehaben A. Gujarati, Bradley J. Undem and Vijaya L. Korlipara* Pages 1 - 10 ( 10 )
Background: Inhibition of transient receptor potential vanilloid receptor 1 (TRPV1) has emerged as a novel approach in 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 was 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 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 biological assay. This observation was further supported by molecular modeling studies using CoMFA.
TRPV1, Pain, Isoquinoline ureas, A-425619, SB 705498, Smooth Muscle Assay
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439