Kenneth Richardson

Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against aspergillus fumigatus.

Abstract Replacement of one triazole ring of fluconazole with 4-pyridinyl leads to an increase in activity against Aspergillus fumigatus. Introduction of an α-methyl group has a marked additional beneficial effect. Investigation of pyridinyl and pyrimidinyl analogues resulted in the identification of 30 (UK-109, 496, voriconazole) which has excellent potency against a broad range of fungal pathogens including A. fumigatus and Candida krusei.

Design and Evaluation of a Systemically Active Agent, Fluconazole

Fungi are all around us. For example, we have Cundida in our gastrointestinal tract and we breathe in fungi such as Cryptococcus and Aspergillus. Despite this, these fungi do not normally cause infections because our bodys defense systems usually protect us. It was realized, however, that certain important medical advances were being accompanied by increasing numbers of patients being put at risk to these infections. For example, the medical profession was making major clinical advances and hence preventing patients dying from leukemia and certain types of cancer, and there were increasing numbers of patients receiving organ transplants. All of these patients were immunosuppressed to some extent and were susceptible to both bacterial and fungal infections. Although there were many powerful and safe antibacterial agents, this was not the case with antifungals. The agents available were amphotericin B and 5fluorocytosine. Amphotericin B, although it can be lifesaving, has to be given by slow intravenous infusion, and side effects (fever, nausea, renal toxicity) tend to make it an agent of last resort-when it is frequently too late. 5-Fluorocytosine, although it is orally absorbed, is only active against a limited range of fungi, and resistance can arise during chronic treatment. There was, therefore, a need for a safe, convenient agent to treat these infections, and we anticipated that in the future there would be an even greater need, as immune suppression became routine. In response to this need, a program was initiated in 1978 at Pfizer Central Research in Sandwich to seek an agent suitable for the treatment of life-threatening systemic fungal infections. (In 1978, of course, we could not predict the advent of acquired immune deficiency syndrome and the accompanying increase in systemic fungal infections.) We felt that the ideal drug for the treatment of systemic fungal infections should be effective both orally and intravenously. The usual treatment would be by oral administration; some very ill patients, however, have difficulty with oral dosage forms, and hence an intravenous dosage form would be needed. Clearly, it should also be safe and active against a wide range of fungi. A well-tolerated drug would also allow prophylaxis of patients at risk, to prevent systemic infections occurring (for example, during periods of immunosuppression for organ transplants or during periods of intensive chemotherapy in cancer patients). In addition, a very safe agent would offer

Chapter 16 Antifungal Agents

Publisher Summary Fungal infections in man remain an important cause of morbidity and mortality. Topical treatment of superficial infections is adequate in most cases. However, safe, orally active agents for use in more problematic diseases, for example, extensive dermatophytosis or recurrent fungal vaginitis, are still needed. Despite the advances made in the recent years, the number of drugs with proven efficacy against life-threatening systemic mycoses is small. Thus, the ideal agent, with potent, broadspectrum activity and lacking side effects, is yet to be developed. The chapter discusses the azole anti-fungals and, in particular, on the triazole derivatives. Itraconazole continues to show promise in the oral treatment of superficial and systemic infections. A recent development is fluconazole, a water-soluble triazole derivative that offers, for the first time, the opportunity for both oral and parenteral therapy. In the field of topical azole antifungals, bifonazole has the advantage of once-daily application. Limited studies with liposomal amphotericin B continue to suggest this method of formulation maintains efficacy while reducing toxicity. However, till date no commercial formulation is available. Terbinafine, an orally active allylamine derivative, has shown clinical efficacy in the treatment of dermatophytoses.

Enantiodifferentiation of dihydropyridine PAF antagonists

Abstract The PAF antagonist activity of a series of enantiomeric dihydropyridines is described. In the first example, 1 , the PAF antagonist activity and calcium channel blocking activity reside in opposite enantiomers. Subsequent examples also display enantioselectivity and the SAR of the series is described.