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

Chunjian Liu, James Lin, John Hynes, Hong Wu, Stephen T. Wrobleski, Shuqun Lin, T. G.Murali Dhar, Vivekananda M. Vrudhula, Jung Hui Sun, Sam Chao, Rulin Zhao, Bei Wang, Bang Chi Chen, Gerry Everlof, Christoph Gesenberg, Hongjian Zhang, Punit H. Marathe, Kim W. McIntyre, Tracy L. Taylor, Kathleen GilloolyDavid J. Shuster, Murray McKinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7775-7784
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number19
DOIs
StatePublished - Oct 8 2015

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Prodrugs
p38 Mitogen-Activated Protein Kinases
Experimental Arthritis
Esterases
Solubility
Alkaline Phosphatase
Acetates
Phosphates
((4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo(1,2-f)(1,2,4)triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate
Water
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / 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: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 19. pp. 7775-7784.
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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",
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.",
author = "Chunjian Liu and James Lin and John Hynes and Hong Wu and Wrobleski, {Stephen T.} and Shuqun Lin and Dhar, {T. G.Murali} and Vrudhula, {Vivekananda M.} and Sun, {Jung Hui} and Sam Chao and Rulin Zhao and Bei Wang and Chen, {Bang Chi} and Gerry Everlof and Christoph Gesenberg and Hongjian Zhang and Marathe, {Punit H.} and McIntyre, {Kim W.} and Taylor, {Tracy L.} and Kathleen Gillooly and Shuster, {David J.} and Murray McKinnon and Dodd, {John H.} and Barrish, {Joel C.} and Schieven, {Gary L.} and Katerina Leftheris",
year = "2015",
month = "10",
day = "8",
doi = "10.1021/acs.jmedchem.5b00839",
language = "English (US)",
volume = "58",
pages = "7775--7784",
journal = "Journal of Medicinal Chemistry",
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publisher = "American Chemical Society",
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Liu, C, Lin, J, Hynes, J, Wu, H, Wrobleski, ST, Lin, S, Dhar, TGM, Vrudhula, VM, Sun, JH, Chao, S, Zhao, R, Wang, B, Chen, BC, Everlof, G, Gesenberg, C, Zhang, H, Marathe, PH, McIntyre, KW, Taylor, TL, Gillooly, K, Shuster, DJ, McKinnon, M, Dodd, JH, Barrish, JC, Schieven, GL & Leftheris, K 2015, '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', Journal of Medicinal Chemistry, vol. 58, no. 19, pp. 7775-7784. https://doi.org/10.1021/acs.jmedchem.5b00839

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. / 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.

In: Journal of Medicinal Chemistry, Vol. 58, No. 19, 08.10.2015, p. 7775-7784.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Liu, Chunjian

AU - Lin, James

AU - Hynes, John

AU - Wu, Hong

AU - Wrobleski, Stephen T.

AU - Lin, Shuqun

AU - Dhar, T. G.Murali

AU - Vrudhula, Vivekananda M.

AU - Sun, Jung Hui

AU - Chao, Sam

AU - Zhao, Rulin

AU - Wang, Bei

AU - Chen, Bang Chi

AU - Everlof, Gerry

AU - Gesenberg, Christoph

AU - Zhang, Hongjian

AU - Marathe, Punit H.

AU - McIntyre, Kim W.

AU - Taylor, Tracy L.

AU - Gillooly, Kathleen

AU - Shuster, David J.

AU - McKinnon, Murray

AU - Dodd, John H.

AU - Barrish, Joel C.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2015/10/8

Y1 - 2015/10/8

N2 - 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.

AB - 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.

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U2 - 10.1021/acs.jmedchem.5b00839

DO - 10.1021/acs.jmedchem.5b00839

M3 - Article

C2 - 26359680

AN - SCOPUS:84943775745

VL - 58

SP - 7775

EP - 7784

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 19

ER -