Description: BMS-751324 is a novel prodrug of BMS-582949 (also known as PS540446) which is a potent and highly selective p38 mitogen-activated protein kinase (p38 MAPK) inhibitor with IC50 of 13nM and is currently in phase II clinical trials for the treatment of rheumatoid arthritis. BMS-751324 was discovered in search for prodrugs to address the issue of pH-dependent solubility and exposure associated with BMS-582949, a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug. BMS-751324 has a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities. BMS-751324 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug BMS-582949 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of BMS-582949 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, BMS-751324 demonstrated similar efficacy to BMS-582949. Most importantly, it was shown in clinical studies that BMS-751324 was indeed effective in addressing the pH-dependent absorption issue associated with BMS-582949.