MDL 201,307: a novel benzothiazepine modulator of multiple drug resistance.

A series of novel benzothiazepine derivatives were evaluated for their relative potential to reverse multiple drug resistance (MDR) phenotype in vitro as well as for their relative cardiovascular activity and neurotoxicity. Compounds were evaluated for antiMDR activity using Chinese hamster ovary cells with derived resistance to either vincristine or doxorubicin, or a human lymphoblastic leukemia line with resistance to vinblastine. Lead compounds with good antiMDR activity were further evaluated for their relative potential to exhibit cardiovascular and neurological pharmacodynamic activity. A single compound, MDL 201,307 with good antiMDR activity and low cardiovascular and neurologic activity was chosen for further study. In contrast to (R)-verapamil, MDL 201,307 showed only a weak potential to block calcium channels. Using a series of related murine fibrosarcoma cell lines (UV-2237M) with varying levels of resistance to doxorubicin, it was shown that MDL 201,307 augmented inhibition of growth due to doxorubicin. The antiMDR compound was also effective in enhancing the cytotoxicity of actinomycin-D and vinblastine although it was ineffective in increasing cytotoxicity of the nonMDR compound, 5FU. MDL 201,307 increased uptake and decreased efflux of doxorubicin suggesting that MDL 201,307 blocks the GP170-mediated efflux pump mechanism. MDL 201,307 represents a novel antiMDR agent with diminished potential for cardiovascular activity and neurologic interactions which presently limit many of the currently available first and second generations of antiMDR compounds.