Abstract：
SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies.
摘要：
SMP-028是一种用于治疗哮喘的候选药物。在SMP-028对大鼠和猴子的13周重复剂量毒性研究中，观察大鼠和猴内分泌毒理事件的差异。在老鼠身上,这些毒理学事件主要包括肾上腺的病理变化，睾丸,子房,和其他内分泌相关器官。另一方面,在猴子身上,未观察到毒理学事件.这项研究的目的是试图理解为什么只有老鼠，但不是猴子，显示用SMP-028治疗后的毒理学事件，并最终预测该化合物对人体内分泌器官的可能毒理学作用。我们的结果表明，SMP-028比其他类固醇生成酶更强烈地抑制大鼠的中性胆固醇酯酶。虽然SMP-028也抑制猴子和人类中性胆固醇酯酶，这种抑制作用比大鼠中性胆固醇酯酶弱得多。这些结果表明（1）大鼠和猴子之间的内分泌毒理学事件的差异主要是由于SMP-028对大鼠类固醇生成的抑制，不是在猴子身上，和（2）SMP-028可能不会影响人类的类固醇生成，因此在临床研究中可能不会引起内分泌毒理学事件。
