RESUMEN
Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development.
Asunto(s)
Antimitóticos/uso terapéutico , Hidrocarburos Halogenados/uso terapéutico , Microtúbulos/efectos de los fármacos , Triazoles/uso terapéutico , Animales , Antimitóticos/efectos adversos , Antimitóticos/metabolismo , Antimitóticos/farmacocinética , Antimitóticos/farmacología , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase I como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Hidrocarburos Halogenados/efectos adversos , Hidrocarburos Halogenados/metabolismo , Hidrocarburos Halogenados/farmacocinética , Hidrocarburos Halogenados/farmacología , Ratones , Neoplasias/tratamiento farmacológico , Ratas , Triazoles/efectos adversos , Triazoles/metabolismo , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.