History of Azole Discovery

azoles were the first purely synthetic class of antifungal agents to be exploited clinically, and their discovery was facilitated by the search for agents for use in the control of fungi in an agrochemical context, where they have had an equally dramatic impact. Thus early antifungal screens soon established that simple imidazole derivatives had activity, building on the first (serendipitous) observation by Woolley in 1944 that benzimidazole affected fungal growth in vitro (29). Of the very many agents that have been reported, the chronology of discovery of the most significant clinically is highlighted below.

The first azole to become available for clinical use (as a topical agent) was chlormidazole (Fig. 17.3), introduced by Chemie Gru-enenthal in 1958. It was followed in 1969 by Janssen's miconazole (30) and Bayer's clotrimazole (31), and econazole (30) was launched by Janssen in 1974. Even today, the latter three agents remain the mainstay of topical therapy for many dermatophytoses.

In the late 1970s and 1980s, the emphasis in research in anti-infectives was toward the identification of antibacterial agents, in that the clinical need was particularly evident in that area. The only significant event in the fungal context was the introduction by Janssen in 1981 of ketoconazole, the first azole with utility in the treatment of systemic my-Like its forebears, this agent is an imidazole derivative, albeit of significantly greater structural complexity; the dioxolane ring was first incorporated in much simpler acetophenone derivatives that were reported as part of the miconazole discovery effort (33). It proved a significant advance in the treatment of serious fungal disease in that it provided an orally available, less toxic alternative to amphotericin B, and for nearly 10 years was the only azole available for this purpose. As such, it saw widespread use, despite limitations with respect to bioavailability and pharmacokinetic interactions (see below).

The finding that imidazole could be replaced by triazole as the C14-demethylase heme-coordinating ligand was a major breakthrough because it provided both greater selectivity for the fungal enzyme and greater metabolic stability in vivo. The issue of selec tivity was a particular concern, given the ubiquity of CyP450-mediated enzymes in mammalian systems and the attendant association of azoles with hepatic side effects and effects on hormone synthesis. Janssen's itraconazole made use of this key change (33), although the extended ketoconazole-like side chain rendered the compound extremely insoluble, presenting formidable challenges in identifying formulations that allowed parenteral administration or gave reliable oral bioavailability. Thus, despite the appearance on the market of an oral capsule form in 1992, an oral solution in cyclodextrin was not launched until 1997, and it took until 1999 for an intravenous formulation (inhydroxypropyl-j8-cyclodextrin) to become available.

The discovery of fluconazole at Pfizer was an interestingstudy in the optimization of molecular properties important for good activity in vivo. As with most azole discovery programs at this time, a mouse survival model involving challenge with a lethal, systemic dose of C. albicans was being used at an early stage in the evaluation process to differentiate analogs. The use of the triazole moiety was based on the reduced propensity for first-pass metabolism, and the emphasis on analogs containing a tertiary alcohol (as opposed to diox-olanes or tetrahydrofurans) was also based on the superior activity observed in vivo. A conscious attempt was made to focus on polar analogs, particularly with regard to the side chain, thereby minimizing serum protein binding and maximizing the amount of unbound drug available at the site of infection; it was this consideration that led to the incorporation of a second azole moiety into the molecule. Finally, systematic variation of the halo-substituted aromatic group, combined with pharmacokinetic studies in mice, led to the selection of the 2,4-difluorophenyl analog, which was notable for its high urinary recovery (indicative of metabolic stability) (34). This discovery strategy has been fully vindicated: the solubility, safety, and predictable pharmacokinetics of fluconazole, launched in 1991, have driven its success as the world's predominant prescription antifungal agent.

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  • nob
    When were azoles launched?
    1 month ago

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