Structure-activity relationships in the induction of mammary gland neoplasia in male rats with substituted aminopyrazoles.

In toxicity studies with a potential antipsychotic agent, N-(4-[2-fluorobenzoyl]-1,3-dimethyl-1H-pyrazol-5-yl)-2-([3- (2-methyl-1-piperidinyl)propyl]amino)-acetamide(Z)-2-butenedioate (1:2) (FP-1), mammary gland neoplasia in male rats was induced within 13 weeks. Tumor induction by the parent compound (FP-1) and structural analogs was also explored. Rats were given 50 mg/kg/day of FP-1 or the diethyl glycine analog, FP-2. Other experimental groups received the FP nucleus, a benzoylpyrazolylacetamide, or the FP side chains alone or administered concurrently with the nucleus. Most animals survived the 13 weeks without significant clinical effects. Clinically detectable, gross subcutaneous mammary nodules developed only in rats given FP-1 or the FP nucleus coadministered with the FP-1 side chain. Additional mammary gland neoplasms were found at necropsy or on histopathologic examination of mammary glands from rats receiving FP-1, FP-2, and the FP nucleus. The neoplastic effect was not influenced by the structure of the side chains. Since these substituted aminopyrazoles are novel chemicals, the mechanism for this neoplastic effect is not yet clearly established; however, the proliferating effect resides in the nucleus of this series of compounds and is likely related to alteration of DNA in target mammary tissue.