Efficient Synthesis of Impurity-C of Antimigraine Agent Rizatriptan Benzoate

During the commercial manufacturing of antimigraine drug Rizatriptan benzoate, several impurities are reported to be formed. This present work demonstrates a convergent and short synthesis of the most critical impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-yl)­methyl)-1H-indole-2-yl)-<i>N</i>,<i>N</i>-dimethylethanamine (<b>1</b>)], recently reported in U.S. Pharmacopeia

Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines

A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their <i>in vitro</i> potency) when evaluated further for <i>in vitro</i> metabolic stability as well as pharmacokinetic profile led to the identification of <b>26</b>, as a candidate for further development. The IC₅₀ and EC₅₀ value of <b>26</b> is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound <b>26</b>, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days