Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance

OC144-093 is a novel substituted diarylimidazole (M-r 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed m ultidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in hu man lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 mu M. Inhib ition of MDR by OC144-093 was reversible, but the effect persisted for at l east 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-g p expression or expressing a multidrug resistance-associated protein (MRP-1 ). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 mu M. OC144-093 blocked the binding of [H-3]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.- administered paclitaxel. OC144-093 increased the life span of doxorubicin-t reated mice engrafted with MDR P388 leukemia cells by >100% and significant ly enhanced the in vivo antitumor activity of paclitaxel in MDR human breas t and colon carcinoma xenograft models, without a significant increase in d oxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 i s an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidr ug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/ or induction of refractory disease.