Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2‑f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor
In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hy...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-10, Vol.58 (19), p.7775-7784 |
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| container_title | Journal of medicinal chemistry |
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| creator | Liu, Chunjian Lin, James Hynes, John Wu, Hong Wrobleski, Stephen T. Lin, Shuqun Dhar, T. G. Murali Vrudhula, Vivekananda M. Sun, Jung-Hui Chao, Sam Zhao, Rulin Wang, Bei Chen, Bang-Chi Everlof, Gerry Gesenberg, Christoph Zhang, Hongjian Marathe, Punit H. McIntyre, Kim W. Taylor, Tracy L. Gillooly, Kathleen Shuster, David J. McKinnon, Murray Dodd, John H. Barrish, Joel C. Schieven, Gary L. Leftheris, Katerina |
| description | In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1. |
| doi_str_mv | 10.1021/acs.jmedchem.5b00839 |
| format | Article |
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G. Murali ; Vrudhula, Vivekananda M. ; Sun, Jung-Hui ; Chao, Sam ; Zhao, Rulin ; Wang, Bei ; Chen, Bang-Chi ; Everlof, Gerry ; Gesenberg, Christoph ; Zhang, Hongjian ; Marathe, Punit H. ; McIntyre, Kim W. ; Taylor, Tracy L. ; Gillooly, Kathleen ; Shuster, David J. ; McKinnon, Murray ; Dodd, John H. ; Barrish, Joel C. ; Schieven, Gary L. ; Leftheris, Katerina</creator><creatorcontrib>Liu, Chunjian ; Lin, James ; Hynes, John ; Wu, Hong ; Wrobleski, Stephen T. ; Lin, Shuqun ; Dhar, T. G. Murali ; Vrudhula, Vivekananda M. ; Sun, Jung-Hui ; Chao, Sam ; Zhao, Rulin ; Wang, Bei ; Chen, Bang-Chi ; Everlof, Gerry ; Gesenberg, Christoph ; Zhang, Hongjian ; Marathe, Punit H. ; McIntyre, Kim W. ; Taylor, Tracy L. ; Gillooly, Kathleen ; Shuster, David J. ; McKinnon, Murray ; Dodd, John H. ; Barrish, Joel C. ; Schieven, Gary L. ; Leftheris, Katerina</creatorcontrib><description>In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. 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G. Murali</au><au>Vrudhula, Vivekananda M.</au><au>Sun, Jung-Hui</au><au>Chao, Sam</au><au>Zhao, Rulin</au><au>Wang, Bei</au><au>Chen, Bang-Chi</au><au>Everlof, Gerry</au><au>Gesenberg, Christoph</au><au>Zhang, Hongjian</au><au>Marathe, Punit H.</au><au>McIntyre, Kim W.</au><au>Taylor, Tracy L.</au><au>Gillooly, Kathleen</au><au>Shuster, David J.</au><au>McKinnon, Murray</au><au>Dodd, John H.</au><au>Barrish, Joel C.</au><au>Schieven, Gary L.</au><au>Leftheris, Katerina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2‑f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-10-08</date><risdate>2015</risdate><volume>58</volume><issue>19</issue><spage>7775</spage><epage>7784</epage><pages>7775-7784</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.jmedchem.5b00839</doi></addata></record> |
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| source | ACS Publications |
| title | Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2‑f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor |
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