Activity of SM-4470, a new imidazole derivative, against experimental fungal infections

Abstract

The antifungal activity of orally active SM-4470, (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazole-1-yl)-Z-propanol hydrochloride, was compared with that of ketoconazole. SM-4470 showed twofold-higher activity than ketoconazole in the oral treatment of systemic infection with Candida albicans in mice. In addition, SM-4470 was effective against aspergillosis in mice, but ketoconazole was ineffective. The efficacy of SM-4470 was similar to that of ketoconazole in curing experimental candidal vaginitis in rats and trichophytosis in guinea pigs, although its serum concentrations in these animals were lower than those of ketoconazole. These data suggest that SM-4470 may be of value in the treatment of both systemic and superficial fungal infections in humans.Several new imidazole and triazole antifungal agents have been developed in the last few years. These are effective topically in the treatment of dermatophytosis and vaginal candidiasis, but ketoconazole is the only commercially available imidazole that is orally effective against these infections (3-5). Ketoconazole has shown variable activity against life-threatening systemic infections (3); the polyene amphotericin B is still used for treating these infections, but its use is limited by toxicity and the need to give it by intravenous infusion. The other agent of significance is 5-fluorocytosine, which has a limited spectrum of antifungal activity, and its use in therapy frequently leads to the emergence of resistant strains. We recently succeeded in developing SM-4470 (Fig. 1), a new imidazole derivative. In this report we compare its activity with that of ketoconazole against experimental systemic and superficial infections in laboratory animals. MATERIALS AND METHODSFungi. All fungi used in these studies were from the culture collection in our laboratory. Cultures of these organisms were freeze-dried and stored, and subcultures on Sabouraud dextrose agar (SDA) were made as needed. Candida albicans and Aspergillus fumigatus strains were grown at 30°C on SDA with 5% rabbit blood for 3 days, and Trichophyton mentagrophytes was grown on SDA at 30°C for 7 days.Compounds. SM-4470 and ketoconazole were synthesized in the Research Laboratories, Sumitomo Pharmaceuticals Co. For this experimental study, both compounds were formulated as suspensions in 0.5% methylcellulose solution. This gave reproducible, homogeneous drug dispersions for the comparative studies.Laboratory animals. Male albino mice of the strains ICR and ddY

In vivo efficacy of SM-8668 (Sch 39304), a new oral triazole antifungal agent

“…A number of azole derivatives that are active against experimental fungal infection after oral administration have been reported in recent years (4,7,8,11,14,16,17), and two of them (fluconazole and itraconazole) have been released for use. These compounds both show higher efficacy and lower toxicity than ketoconazole in laboratory animals (3,16,20,24).…”

“…We previously reported on SM-4470, an imidazole derivative (11), and have continued to screen azole derivatives for their activity against systemic candidiasis in mice. These studies led to the detection of SM-8668, a new oral triazole derivative ( Fig.…”