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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Liu C,Lin J,Hynes J,Wu H,Wrobleski ST,Lin S,Dhar TG,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,Bardoi
10.1021/acs.jmedchem.5b00839subject
Has Abstractpub_date
2015-10-08 00:00:00pages
7775-84issue
19eissn
0022-2623issn
1520-4804journal_volume
58pub_type
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