Effect of Certain 2,4-Diaminopyrimidine Antagonists of Folic Acid on Pregnancy and Rat Fetus. ∗

Summary

(1) 2, 4-diamino-5(3',4'-dichlorophenyl)-6-methylpyrimidine when given to pregnant rats in the doses described, prior to implantation, did not prevent implantation, but led to stunting or fetal death following implantation. When the compound was given following implantation a stunting or lethal effect on the fetuses was achieved depending on the amount of drug administered. The effect on the fetuses could be moderated with a higher yield of live litters but also of stunted and malformed animals when the mother rat was given leucovorin at the time of drug administration. (2) 2,4-diamino-5-p-chlorophenyl-6-ethylpyrimidine had a similar effect on the fetuses in 5 times higher concentration. (3) The malformations induced were similar to those obtained with structurally closely-related folic acid analogues. They consisted in general stunting of growth, general hydrops, cranial bone defects, incomplete cranial and brain development, rachischisis, internal hydrocephalus, ventral hernias, situs inversus, and a combination of all. No live fetuses were obtained from treated mothers who did not gain more than 8% of total body weight during the period of gestation.