ici-195739 and Candidiasis--Vulvovaginal

Antifungal azole derivatives are known to have potential for inhibition of host P-450 systems, and, in the attempts to increase the antifungal specificity of the inhibitor by identification of extra receptor binding within the enzyme complex, initial synthesis was guided by the structural requirements of the natural lanosterol substrate. With the aid of computer graphics, the 3'-styryl functionality was identified as a key structural element. For metabolically stable systems, in vitro-in vivo correlations exist, but optimizing oral activity resulted in the production of compounds with unacceptably long elimination half-lives. A disconnection of this relationship was achieved in pairs of structural isosteres with metabolic nonequivalence (CN:CONH2/OCH3:OCF3) and led to the identification of ICI 195,739, a novel 3'-tetrafluoropropoxystyryl-substituted bistriazole tertiary alcohol, as the compound of choice.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis, Vulvovaginal; Female; Mice; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Triazoles

ICI 195,739 shows superior potency to other azoles in eliminating vaginal candidosis or dermatophyte infections in animal models of infection by both oral dosing and topical application; effective doses are in the range of 0.5-5.0 mg/kg/day or 0.01-0.30% in a topical formulation. ICI 195,739 is likewise effective in models of systemic fungal infection; 1, 10, 25 mg/kg/day will protect animals given a lethal inoculum of C. albicans, C. neoformans, or A. fumigatus, respectively, as long as dosing is continued, showing activity in this respect superior to that of other azoles tested. ICI 195,739 will suppress infections in mice with T. cruzi and prevent mortality with five daily doses of 1 mg/kg; cure rather than suppression of patent infections has been achieved with 35 daily doses of 10 mg/kg.

Topics: Animals; Antifungal Agents; Antiprotozoal Agents; Candidiasis, Vulvovaginal; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Malaria; Mice; Rats; Structure-Activity Relationship; Tinea; Triazoles; Trypanosomiasis