Routine in vitro screening of a new synthetic series of 3,5-substituted 2-methylisoxazolidines revealed that three
imidazole analogs (
PR 967-248,
PR 967-234, and
PR 969-566) and, to a lesser extent, a
triazole analog (PR 988-399) exerted rather potent antifungal activity against three systemic and four dermatophytic classes of fungi. When tested in vivo for ability to eradicate Candida
vaginitis in the rat, the
triazole derivative, PR 988-399, was effective after
oral administration. In this in vivo test for efficacy,
PR 967-234 and
PR 969-566 reduced but did not eradicate the
infection, while
PR 967-248 was inactive. PR 988-399 was, moreover, 4- to 13-fold less potent than the three
imidazoles in inhibiting
testosterone synthesis in isolated rat Leydig cells. After oral or
intravenous administration, PR 988-399 and
PR 969-566 elicited the fewest cardiovascular and behavioural side effects in conscious dogs. The rat safety study consisted of oral dosing followed by evaluation of the exploratory motor activity of the naive animals in a novel environment. Motor activity was suppressed least by PR 988-399 and most by
PR 969-566. In a battery of mouse behavioural-neuromuscular-drug interaction tests, PR 988-399 and
PR 969-566 produced the fewest central-behavioural-neuromuscular signs. These efficacy-safety evaluations were performed with
ketoconazole as a positive reference standard. The sequence of
drug testing with respect to efficacy-safety considerations appears to be a suitable approach for early detection of orally active
antifungal agents such as PR 988-399 for more advanced development.