RESUMO
Within hours after administration of high oral doses of ketoconazole to males of various species, the intact compound appears in the seminal plasma, leading to immobilization of spermatozoa in ejaculates collected several hours later. The present report describes in vitro and in vivo characterization studies of several new compounds identified from a series of 1-substituted imidazole compounds. Relative rank order of in vitro potencies of the four compounds studied was RS-29984 greater than RS-90847 greater than RS-41353 greater than RS-68287. Oral administration of single doses of these compounds ranging between 10 and 95 mg/kg, followed by ejaculation of the animals at various times after dosing, showed that their relative potencies for decreasing sperm motility were RS-41353 greater than RS-68287 = RS-90847 greater than RS-29984. Four hours after animals were given 30 mg/kg of RS-41353, spermatozoa in the ejaculates had zero forward progression within 30 to 40 minutes after the start of ejaculation. A preliminary metabolic study indicated that the apparently greater potency of RS-68287 in vivo than in vitro was probably not due to metabolic activation. The androgen-suppressing activity of RS-29984 and RS-90847 was shown to be less than that of ketoconazole. These data indicate that orally active inhibitors of sperm motility that exert their effects after ejaculation may be feasible, and suggest that this novel approach to male contraception warrants further investigation.
