RESUMEN
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
RESUMEN
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100â¯nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10â¯mpkâ¯=â¯0⯵Mâ¯h; F%â¯=â¯0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10â¯mpkâ¯=â¯26⯵Mâ¯h; F%â¯=â¯70).
Asunto(s)
Antineoplásicos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirrolidinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N-sulfinylimines is described. Vinyl anions derived from enol triflate 2 undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.