Discovery Of ((4-(5-(Cyclopropylcarbamoyi)-2-Methylphenylamino)-5-Methylpyrrolo[1,2-F ][1,2,4]Triazine-6-Carbonyl)(Propyl)Carbamoyloxy)Methyl-2-(4-(Phosphonoo Xy)Phenyl)Acetate (Bms-751324), A Clinical Prodrug Of P38a 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 p38a 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 TNFa 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 I.