Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science
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Abstract: 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 guniea pig trachea along with evaluation of the molecular properties and molecular modelling using CoMFA studies.
Results: p-Chloro 4, p-bromo 5, m-isothiocyanate 15, and p-isothi...ocyanate 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.
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Medicinal Chemistry, 2018, 1/BMS-MC-2018-211-6Collections
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Mašinski fakultetTY - JOUR AU - Jovanović, Tamara PY - 2018 UR - https://machinery.mas.bg.ac.rs/handle/123456789/6151 AB - Abstract: 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 guniea pig trachea along with evaluation of the molecular properties and molecular modelling 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. T2 - Medicinal Chemistry T1 - Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science EP - 6 SP - 1/BMS-MC-2018-211 UR - https://hdl.handle.net/21.15107/rcub_machinery_6151 ER -
@article{ author = "Jovanović, Tamara", year = "2018", abstract = "Abstract: 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 guniea pig trachea along with evaluation of the molecular properties and molecular modelling 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.", journal = "Medicinal Chemistry", title = "Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science", pages = "6-1/BMS-MC-2018-211", url = "https://hdl.handle.net/21.15107/rcub_machinery_6151" }
Jovanović, T.. (2018). Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science. in Medicinal Chemistry, 1/BMS-MC-2018-211-6. https://hdl.handle.net/21.15107/rcub_machinery_6151
Jovanović T. Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science. in Medicinal Chemistry. 2018;:1/BMS-MC-2018-211-6. https://hdl.handle.net/21.15107/rcub_machinery_6151 .
Jovanović, Tamara, "Review of the article „Design, synthesis, and evaluation of isoquinoline urease as TRPV1 antagonists“, verified by Publons, Web of Science" in Medicinal Chemistry (2018):1/BMS-MC-2018-211-6, https://hdl.handle.net/21.15107/rcub_machinery_6151 .