Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane (1) hydrochloride, are structurally distinct from metalloporphyrin HO inhibitors and lack the aminothiophenol moiety of azalanstat. They were found to be highly selective for the HO-1 isozyme (stress induced) and had substantially less inhibitory potency toward HO-2, the constitutive isozyme. These imidazole-dioxolane compounds are the first of their type known to exhibit this isozyme-selective HO inhibition.

The human multidrug resistance protein 1 (MRP1) is a primary active transporter of reduced (GSH) and oxidized glutathione, as well as GSH-, glucuronate-, and sulfate-conjugated organic anions. In addition, the transport of certain MRP1 substrates is stimulated by the presence of GSH. To evaluate the structural features of GSH required for interaction with the protein, we investigated the ability of a series of GSH analogs to enhance GSH stimulatable transport of [ 3 H]estrone 3-sulfate (E 1 SO 4 ). We found that substitution of the ␥-Glu residue with Gly, ␤-Asp, and ␣-Glu resulted in complete loss of transport stimulation. In contrast, substitution of Gly with Glu or ␤-Ala resulted in only a partial loss of stimulatory activity. E 1 SO 4 transport activity surpassed GSH-stimulated levels in the presence of tripeptides in which Cys was substituted with the hydrophobic amino acids Leu, Phe, and homo-Phe. Moreover, polar substitutions of Cys did not enhance transport to the same extent as nonpolar substitutions of comparable size. ␥-Glu-Leu-Gly was 1.6-fold more effective than GSH in stimulating E 1 SO 4 uptake, and kinetic analysis indicated this was due to an increased V max . In addition, this tripeptide was shown to be a competitive inhibitor of apigenin-stimulated GSH transport (K i value of 14 M), confirming that it either interacts with the same site on MRP1 as GSH or that the binding of the two tripeptides is mutually exclusive. These data provide insight into the architecture of the GSH binding domain of MRP1.

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Imidazole derivatives Imidazole derivatives R 0190Synthesis and Evaluation of Azalanstat Analogues as Heme Oxygenase Inhibitors.-Compounds (VI) show the best selectivity against HO-1 of all tested compounds (some yields not given). -(VLAHAKIS, J. Z.; KINOBE, R. T.; BOWERS, R. J.; BRIEN, J. F.; NAKATSU, K.; SZAREK*, W. A.; Bioorg. Med. Chem. Lett. 15 (2005) 5, 1457-1461; Dep. Chem., Queen's Univ., Kingston, Ont. K7L 3N6, Can.; Eng.) -C. Oppel 28-132