Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN, 55414, USA.
Department of Genetics and Development, USA.
Eur J Med Chem. 2023 Dec 5;261:115821. doi: 10.1016/j.ejmech.2023.115821. Epub 2023 Sep 25.
Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with significant oral bioavailability, metabolic stability, and testes exposure. Compound 21 was evaluated for its effects on spermatogenesis and disruption of fertility in a mouse model. Oral administration of compound 21 at low doses showed reproducibly characteristic albeit modest effects on spermatogenesis, but no effects on fertility were observed in mating studies. The inhibition of spermatogenesis could not be enhanced by raising the dose and lengthening the duration of dosing. Thus, 21 may not be a good candidate to pursue further for effects on male fertility.
本文报道了一系列基于二氢萘和色烯骨架的维甲酸类似物的合成及体外评价，采用的是转激活测定法。色烯酰胺类似物 21 是该系列中鉴定出的最有效和选择性的维甲酸受体 α 拮抗剂。体外评价表明，21 具有良好的理化性质和体内药代动力学 PK 特征，具有显著的口服生物利用度、代谢稳定性和睾丸暴露。对化合物 21 在小鼠模型中对精子发生的影响及其对生育能力的破坏作用进行了评估。低剂量口服给药 21 可重复、特征性地对精子发生产生适度影响，但在交配研究中未观察到对生育能力的影响。增加剂量和延长给药时间并不能增强对精子发生的抑制作用。因此，21 可能不是一个很好的候选药物，无法进一步用于男性生育能力。
