Acrosin inhibitors as vaginal contraceptives in the primate and their acute toxicity

Abstract

The contraceptive acitivity of Delfen vaginal cream in the stumptailed macaque (macaca arctoides) tends to be enhanced by the addition of p-nitrophenyl-p'-guanidino benzoate (NPGB, 9 mg/ml) but not by N-α-p-tosyl-L-lysine chloromethylketone (TLCK, 3 mg/ml). Both compounds are synthetic inhibitors of acrosin, a sperm proteinase involved in the union of the male and female gametes. The addition of NPGB (0.09 mg/ml) to K-Y jelly made this neutral suppository equally or slightly more effective than Delfen vaginal cream. The addition of TLCK (3 mg/ml) or antipain (0.9 mg/ml), a naturally occurring inhibitor of acrosin, did not cause K-Y jelly to have contraceptive activity but 10 mg/ml TLCK did. The inhibitors had little or no effect on the postcoital motility of the spermatozoa, did not influence the length of pregnancy and had no toxic effects in the primates. NPGB and 2 other low molecular weight acrosin inhibitors, aminobenzamidine and benzamidine, were evaluated for acute toxicity by intraperitoneal injection into mice. The 3 compounds had LD(50) values of 180, 240 and 580 mg/kg BW, respectively. Thus, the toxic dose of these compounds is 1,000-10,000 times greater than the concentration at which they exert antifertility activity. The results encourage the continued development and evaluation of acrosin inhibitors as contraceptive agents for human use.