Effects of SCH 486757, a nociceptin-1 receptor agonist, on fertility and reproductive hormone levels in female CRL:CD®[SD] rats.

BACKGROUND: SCH 486757 is a nociceptin-1 receptor agonist that was in development as an antitussive. Studies were conducted to characterize its effects on female fertility and to examine its potential modes of action. METHODS: Female rats were administered up to 20 mg/kg SCH 486757 before/during mating through gestation day (GD) 7; female fertility and embryonic development were assessed on GD 14. In a subsequent study, pregnant rats were dosed up to 50 mg/kg SCH 486757 from GD 0 to 7. Reproductive hormones were assessed on GD 1, 3, 5, and 7, and embryonic development was assessed on GD 14. A subset of dosed dams were allowed to deliver, were subsequently re-mated, and reproductive hormones and fertility were assessed on GD 7 and 14, respectively. To determine the effects of SCH 486757 on nonpregnant rats, doses of up to 50 mg/kg SCH 486757 were administered for 4 days beginning on the day of estrus; reproductive hormones were assessed after the final dose. RESULTS: Female rats administered ≥20 mg/kg SCH 486757 exhibited abnormal estrous cycles; decreased fertility, number of corpora lutea, and implantation sites; and increased pre- and postimplantation loss. In general, administration of SCH486757 was associated with lower luteinizing hormone (LH) progesterone (P4), and estradiol (E2) levels in pregnant rats. These effects on fertility/embryonic development and reproductive hormones exhibited reversibility post dosing. Nonpregnant rats in the 50-mg/kg group exhibited apparent decreases in P4 and E2 levels, with no apparent effects on LH values. CONCLUSIONS: The SCH 486757-related effects on fertility and embryonic development were likely the result of decreases in P4, E2, and/or LH, rather than being due to decreased prolactin levels.

The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys.

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.