The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Laykea Tafesse - One of the best experts on this subject based on the ideXlab platform.
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trpv1 antagonists a survey of the patent literature
Expert Opinion on Therapeutic Patents, 2006Co-Authors: Donald J. Kyle, Laykea TafesseAbstract:The recent cloning of Vanilloid Receptor 1 (TRPV1) from multiple species, together with published results showing efficacy of TRPV1 antagonists in animal models of pain, has led to substantial patenting activity by several major pharmaceutical companies and academic institutions. This review is focused on the patent literature related to non-peptidic small molecule TRPV1 antagonists. A total of 105 published patent applications claiming TRPV1 antagonists are reviewed during 2002 – 2005. Human clinical trials using TRPV1 antagonists are in the earliest stages and interest in this approach toward the treatment of various pain conditions appears to be growing annually.
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Synthesis and evaluation of pyridazinylpiperazines as Vanilloid Receptor 1 antagonists
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Kenneth J. Valenzano, Xin Su, Donald J. KyleAbstract:Abstract A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH 5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line. The most potent VR1 antagonists were found to have IC50 values in the range of 9–200 nM with improved pharmaceutical and pharmacological profiles versus the lead BCTC. These compounds represent possible second-generation BCTC analogs.
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4-(2-pyridyl)piperazine-1-carboxamides: potent Vanilloid Receptor 1 antagonists.
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Laykea Tafesse, Khondaker Islam, Sam Victory, Chongwu Zhang, Lori Schmid, Aniket Patel, Mohamed Hachicha, Xiaoming Zhou, Yakov RotshteynAbstract:A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC50=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Gang Wu, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
Kenneth J. Valenzano - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of pyridazinylpiperazines as Vanilloid Receptor 1 antagonists
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Kenneth J. Valenzano, Xin Su, Donald J. KyleAbstract:Abstract A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH 5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line. The most potent VR1 antagonists were found to have IC50 values in the range of 9–200 nM with improved pharmaceutical and pharmacological profiles versus the lead BCTC. These compounds represent possible second-generation BCTC analogs.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Gang Wu, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
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n 4 tertiarybutylphenyl 4 3 cholorphyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties ii in vivo characterization in rat models of inflammatory and neuropathic pai
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: James D Pomonis, Kenneth J. Valenzano, James E Harrison, Lilly Mark, David R Bristol, Katharine WalkerAbstract:The Vanilloid Receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N- (4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2 H )-carbox-amide (BCTC) is a recently described inhibitor of capsaicin- and acid-mediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 μg of capsaicin. In rats with Freund9s complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
Yakov Rotshteyn - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of pyridazinylpiperazines as Vanilloid Receptor 1 antagonists
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Kenneth J. Valenzano, Xin Su, Donald J. KyleAbstract:Abstract A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH 5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line. The most potent VR1 antagonists were found to have IC50 values in the range of 9–200 nM with improved pharmaceutical and pharmacological profiles versus the lead BCTC. These compounds represent possible second-generation BCTC analogs.
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4-(2-pyridyl)piperazine-1-carboxamides: potent Vanilloid Receptor 1 antagonists.
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Laykea Tafesse, Khondaker Islam, Sam Victory, Chongwu Zhang, Lori Schmid, Aniket Patel, Mohamed Hachicha, Xiaoming Zhou, Yakov RotshteynAbstract:A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC50=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Gang Wu, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
Lori Schmid - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of pyridazinylpiperazines as Vanilloid Receptor 1 antagonists
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Kenneth J. Valenzano, Xin Su, Donald J. KyleAbstract:Abstract A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH 5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line. The most potent VR1 antagonists were found to have IC50 values in the range of 9–200 nM with improved pharmaceutical and pharmacological profiles versus the lead BCTC. These compounds represent possible second-generation BCTC analogs.
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4-(2-pyridyl)piperazine-1-carboxamides: potent Vanilloid Receptor 1 antagonists.
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Laykea Tafesse, Khondaker Islam, Sam Victory, Chongwu Zhang, Lori Schmid, Aniket Patel, Mohamed Hachicha, Xiaoming Zhou, Yakov RotshteynAbstract:A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC50=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Gang Wu, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
James T Limberis - One of the best experts on this subject based on the ideXlab platform.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective Vanilloid Receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Gang Wu, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J. Valenzano, Laykea Tafesse, Lori Schmid, Yakov Rotshteyn, Mohamed Hachicha, Elfrida R Grant, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the Vanilloid Receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other Receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.
