Development of novel embryotoxic compounds for interceptive fertility control in the dog

Studies in pregnant rats, hamsters and guinea-pigs with a series of 2-phenyltriazole isoindoles and isoquinolines and related compounds have demonstrated that these agents are potent abortifacients. These compounds were very effective when administered around the time of implantation and less effective even at higher doses when administered several days before or after implantation. Most of the members of these series of compounds are effective with a single injection although the dosage can be 5 or more times as large as that needed for each of 5 daily injections. The least soluble compounds, L-14105 and L-12717 (Lotrifen), have the longest duration due to slow clearance from the injection site and were the most potent abortifacients. Experiments in beagle and mongrel dogs treated with L-10492, L-10503, L-11204 and Lotrifen during various stages of gestation indicated that all were most efficacious when administered around Day 20 of pregnancy. Lotrifen was the most potent. High abortifacient potency and slow release from the injection depot permitted treatment of bitches during any of the first 15 days after mating with a dosage low enough to reduce unwanted side effects to acceptable levels. Toxic manifestations in all species generally were related to the gastrointestinal tract and consisted of reduced feeding, anorexia and loss in body weight, vomiting by non-rodents, congestion of the intestines and in some animals there was blood loss from this tract. The mechanism of activity has not been defined, but the abortifacient activity is primarily limited to the early post-implantation period.