Traceless solid-phase synthesis of 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivatives is described. Thorpe-Ziegler type cyclization of solid supported cyanocarbonimidodithioate with alpha-halo ketones afforded thiazole resin, which were converted to the desired thiazolopyridine resin by the Friedländer protocol under microwave irradiation conditions. After oxidation of sulfides to sulfones, nucleophilic desulfonative substitution with amines gave the target thiazolo[4,5-b]pyridine derivatives in good overall yields.

e Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 l/min/pmol P450, which is a rate 3.9-and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 l/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7-and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.A lbendazole and fenbendazole are benzimidazole compounds used as broad-spectrum anthelmintics against gastrointestinal nematodes and the larval stages of cestodes (1). Benzimidazole anthelmintics are extensively metabolized in domestic animals and humans. Animal and microsomal incubation studies have demonstrated rapid conversion of albendazole and fenbendazole to a sulfoxide metabolite and subsequently a sulfone metabolite (2-6). Sulfoxide metabolites are responsible for the systemic biological activity of benzimidazole drugs (7). Their metabolic patterns and the resultant pharmacokinetic behaviors are relevant in the attainment of high and sustained concentrations of pharmacologically active drugs/metabolites at the target parasite (8). Evidence from microsomal investigations in a number of species suggests that CYP3A4 and flavin-containing monooxygenase (FMO) are major enzymes responsible for the formation of sulfoxide metabolites from albendazole (4, 9, 10) and fenbendazole (4, 5) (Fig. 1). Recently, Lee et al. (11) reported that the rates of albendazole sulfoxide formation from albendazole by the recombinant CYP2J2 (rCYP2J2) isoform were signifi...

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Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity in vitro and attenuated lipopolysaccharide (LPS)-induced bone destruction in vivo . KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase ( Acp5 ), cathepsin K ( Ctsk ), dendritic cell-specific transmembrane protein ( Dcstamp ), and matrix metallopeptidase 9 ( Mmp9 ). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 ( Irf8 ) and B-cell lymphoma 6 ( Bcl6 ). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by Prdm1 ), a repressor for Irf8 and Bcl6 . Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation in vivo . Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.