Morimoto Junki, Miyamoto Kazunori, Ichikawa Yuki, Uchiyama Masanobu, Makishima Makoto, Hashimoto Yuichi, Ishikawa Minoru
Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Sci Rep. 2021 Jun 16;11(1):12697. doi: 10.1038/s41598-021-92028-y.
Decreasing the partition coefficient (LogP) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. Since melting point is related to aqueous solubility, we and other groups have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. Here, we show that converting the symmetrical molecular structure of the clinically used estrogen receptor (ER) antagonist cyclofenil (1) into asymmetrical form by introducing an alkyl group enhances the aqueous solubility. Among the synthesized analogs, the chiral methylated analog (R)-4c shows the highest solubility, being 3.6-fold more soluble than 1 even though its hydrophobicity is increased by the methylation. Furthermore, (R)-4c also showed higher membrane permeability than 1, while retaining a comparable metabolic rate, and equivalent biological activity of the active forms (R)-13a to 2. Further validation of this strategy using lead compounds having symmetric structures is expected.
通过引入亲水性基团来降低分配系数（LogP）是提高候选药物水溶性的传统方法，但并不总是有效。由于熔点与水溶性相关，我们和其他团队已经开发出替代策略，通过化学修饰来减弱固态下的分子间相互作用，从而降低熔点并提高溶解度。在此，我们表明通过引入烷基将临床使用的雌激素受体（ER）拮抗剂环芬尼（1）的对称分子结构转化为不对称形式可提高其水溶性。在合成的类似物中，手性甲基化类似物（R）-4c表现出最高的溶解度，尽管其疏水性因甲基化而增加，但溶解度仍比1高3.6倍。此外，（R）-4c还表现出比1更高的膜通透性，同时保持相当的代谢率以及活性形式（R）-13a与2相当的生物活性。预计使用具有对称结构的先导化合物对该策略进行进一步验证。
