RESUMEN
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Asunto(s)
Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , RatasRESUMEN
Studies were performed to (1) evaluate whether the presence of iron affected the physicochemical properties of mycophenolate mofetil (MMF) and mycophenolic acid (MPA), and (2) determine whether alteration of these properties was indicative of formation of an MMF-iron complex. The solubility, stability (chemical reactivity), and partitioning properties of MMF and MPA were evaluated over a pH range of 2-7 in the presence and absence of ferrous sulfate. In addition, the solubility and partitioning properties of MMF were assessed after the MMF drug product, CellCept capsules, was combined with an iron tablet (Fero-Gradumet, ferrous sulfate, tablets). The results of studies showed that: The solubility of MMF in the presence of ferrous sulfate was generally unaffected over a pH range of 2-7; a small increase in solubility was observed in pH 5.2 buffer solution. The solubility of MPA decreased in pH 5.2 and 7.0 buffer solutions. Both MMF and MPA were more stable in the presence of ferrous sulfate at pH 2.0; ferrous sulfate had no effect on the stability of MMF and MPA at pH 7.0. Overall, the partitioning of MMF and MPA was unaffected by the addition of ferrous sulfate. The solubility and partitioning of MMF from CellCept capsules combined with Fero-Gradumet (ferrous sulfate) tablets showed a twofold increase in aqueous solubility of MMF as well as increased concentration of MMF in both the n-octanol and aqueous phases, leading to a decrease in the octanol/water partition coefficient due to a reduction in pH of the aqueous phase. Based on these results, it was concluded that the physicochemical properties of MMF and MPA were generally not affected by the presence of ferrous sulfate. Further, the presence of ferrous sulfate did not suggest the formation of an MMF-iron complex.