Shinagawa Yuko, Inoue Teruhiko, Katsushima Takeo, Kiguchi Toshihiro, Ikenogami Taku, Ogawa Naoki, Fukuda Kenji, Hirata Kazuyuki, Harada Kazuhito, Takagi Masaki, Nakagawa Takashi, Kimura Shuichi, Matsuo Yushi, Maekawa Mariko, Hayashi Mikio, Soejima Yuki, Takahashi Mitsuru, Shindo Masanori, Hashimoto Hiromasa
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
ACS Med Chem Lett. 2010 Dec 29;2(3):238-42. doi: 10.1021/ml100268k. eCollection 2011 Mar 10.
Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.
短效口服钙敏感受体（CaSR）拮抗剂——钙溶解剂，已被视为甲状旁腺激素（PTH）的替代药物，PTH是一种用于治疗骨质疏松症的注射用骨合成代谢药物。此前，我们鉴定出氨丙二醇1，它能短暂刺激大鼠内源性PTH分泌。然而，细胞色素P450（CYP）2D6的抑制作用以及1的低生物利用度仍有待解决。通过引入羧酸基团以及进一步的结构修饰来改变高亲脂性胺1的物理化学性质的尝试，导致发现了高效的联苯羧酸15，其对CYP2D6的抑制作用明显降低，生物利用度显著提高。化合物15在大鼠口服给药后，以低至1 mg/kg的剂量呈剂量依赖性地引起内源性PTH水平快速且短暂的升高。PTH分泌模式与药代动力学特征相关，并且与发挥骨合成代谢作用的外源性PTH注射的模式非常吻合。
