OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening.
OC144-093 reversed multidrug resistance (MDR) to
doxorubicin,
paclitaxel, and
vinblastine in human
lymphoma, breast, ovarian, uterine, and
colorectal carcinoma cell lines expressing
P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by
OC144-093 was reversible, but the effect persisted for at least 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-gp 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 microM.
OC144-093 blocked the binding of [3H]
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-treated mice engrafted with MDR
P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of
paclitaxel in MDR human breast and colon
carcinoma xenograft models, without a significant increase in
doxorubicin or
paclitaxel toxicity. The results demonstrate that
OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug 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.