2,4,5-Trisubstituted imidazoles: novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 1.

N-4,5-Di-(4-dialkylamino)phenyl imidazoles (A) are potent modulators of P-glycoprotein mediated multidrug resistance. This manuscript describes the discovery and lead optimization of this novel class of inhibitors.

2,4,5-Trisubstituted imidazoles: novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2.

Solution-phase combinatorial chemistry was applied to the optimization and development of clinical candidate OC144-093 (22), a novel and nontoxic modulator of P-glycoprotein mediated multidrug resistance.

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

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.

A review of carbon disulfide exposure data and the association between carbon disulfide exposure and ischemic heart disease mortality.

Recent regulatory efforts have devoted attention to carbon disulfide (CS2) exposure and its potential effects on the cardiovascular system. To investigate the association between CS2 exposure and ischemic heart disease (IHD) mortality, the analysis presented here had the following objectives: (i) to review historical CS2 exposure data in the viscose rayon industry and identify trends and (ii) to use these historical data to suggest a standard mortality ratio (SMR)-exposure relationship and a threshold level for occupational exposure to CS2, CS2 exposure data were extracted from published studies and used with the SMR versus exposure score relationship developed by Sweetnam et al. (Br. J. Ind. Med. 44, 220-227, 1987) to relate SMRs directly to exposure. Upper and lower bound exposure profiles were derived and used to identify exposure thresholds. For an IHD SMR equal to 100, the upper and lower bound exposures were 60 and 20 ppm, respectively. The analysis indicates that the risk of IHD mortality and its relationship to CS2 exposure is meaningful only for workers exposed to high level for many years. These high levels, which existed many years ago, are no longer found in the workplace. The results of this analysis suggest a safe regulatory exposure level for CS2 between 15 and 20 ppm.

A benchmark concentration for carbon disulfide: analysis of the NIOSH carbon disulfide exposure database.

A statistical analysis of the NIOSH (National Institute for Occupational Safety and Health) carbon disulfide (CS2) exposure database was conducted for purposes of establishing a benchmark concentration (BMC) for CS2. The analysis addressed the effects of CS2 exposure on the peripheral nervous system and on ischemic heart disease risk factors. The BMC is based on models relating response to exposure determined from statistical analysis of the continuous exposure data for individuals recorded in the NIOSH database. The results demonstrate that changes in the responses associated with increases in CS2 exposure at levels represented in the NIOSH database are relatively small after adjustment for confounders. The only response variables that had statistically significant relationships with CS2 were the peroneal nerve MCV (motor conduction velocity) and the peroneal nerve amplitude ratio. Based on these results, BMCs of 16.2 and 18.5 ppm were derived for MCV and amplitude ratio, respectively.

Novel biopolymers for drug discovery.

The solid phase synthesis and generation of libraries of "unnatural biopolymers" is described. These polymers are characterized by novel backbones and building blocks, the properties of which may modify their pharmacological and folding properties.

An unnatural biopolymer.

A highly efficient method has been developed for the solid-phase synthesis of an "unnatural biopolymer" consisting of chiral aminocarbonate monomers linked via a carbamate backbone. Oligocarbamates were synthesized from N-protected p-nitrophenyl carbonate monomers, substituted with a variety of side chains, with greater than 99 percent overall coupling efficiencies per step. A spatially defined library of oligocarbamates was generated by using photochemical methods and screened for binding affinity to a monoclonal antibody. A number of high-affinity ligands were then synthesized and analyzed in solution with respect to their inhibition concentration values, water/octanol partitioning coefficients, and proteolytic stability. These and other unnatural polymers may provide new frameworks for drug development and for testing theories of protein and peptide folding and structure.

Can CEOs survive medical staff opposition?

The odds are stacked against CEOs who hope their jobs will survive embattled relations with their medical staffs. An estimated 50 to 75 percent of CEOs who are fired lose their jobs as a direct result of medical staff conflicts. Some CEOs who have survived such conflicts say that the key is finding unusual solutions to conventional problems.