VNPP433-3β，一种新型育亨宾类似物的小鼠毒理学和药代动力学研究
Murine toxicology and pharmacokinetics of lead next generation galeterone analog, VNPP433-3β.
机构信息
Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Isoprene Pharmaceuticals, Inc., 801 W. Baltimore Street, Suite 502J, Baltimore, MD 21201, USA.
出版信息
Steroids. 2023 Apr;192:109184. doi: 10.1016/j.steroids.2023.109184. Epub 2023 Jan 24.
VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Compound 2 is currently in development as potential new therapeutic for prostate and pancreatic cancers. The preliminary toxicity study reveals that the compound 2 was better tolerated by the normal male CD-1 mice than the male Nude mice. The maximum tolerated dose (MTD) in the Nude mice was estimated to be between 25 < 50 mg/kg. After oral dosing of compound 2 to male and female rats, the plasma concentration versus time curves were very consistent between animals and the AUC increased with dose. Many plasmas concentration versus time curves profiles were nearly flat over 24 hr., suggesting extended absorption from the GI tract. Consequently, reliable values for half-life and AUC were not determined. Calculated oral bioavailability (using oral AUC and excluding the outlier IV animal) ranged from 32 to 47 %. This should be considered a minimum value since the contribution to true AUC beyond 24 hr. is clearly not zero. Clearly, these toxicology and pharmacokinetics parameters pave the way for understanding the anticancer pharmacological actions and provide a meaningful basis for further preclinical development and eventual clinical development.
VNPP433-3β（化合物 2，（3β-（1H-咪唑-1-基）-17-（1H-苯并咪唑-1-基）雄甾-5,16-二烯），是一种多靶标抗癌药物，已成为我们的新一代加特勒酮类似物（NGGA）的先导化合物。化合物 2 目前正在开发中，作为前列腺癌和胰腺癌的潜在新疗法。初步毒性研究表明，该化合物 2 在正常雄性 CD-1 小鼠中的耐受性优于雄性裸鼠。裸鼠的最大耐受剂量（MTD）估计在 25<50mg/kg 之间。雄性和雌性大鼠口服给予化合物 2 后，动物之间的血浆浓度-时间曲线非常一致，AUC 随剂量增加而增加。许多血浆浓度-时间曲线曲线在 24 小时内几乎呈平坦状，表明从胃肠道吸收延长。因此，半衰期和 AUC 的可靠值无法确定。计算的口服生物利用度（使用口服 AUC 并排除 IV 动物的异常值）范围为 32%至 47%。这应被视为最小值，因为 24 小时后对真实 AUC 的贡献显然不为零。显然，这些毒理学和药代动力学参数为了解抗癌药理作用铺平了道路，并为进一步的临床前开发和最终的临床开发提供了有意义的基础。
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