发现新型、有效、口服生物利用度的吡啶并[2,3-d][1]苯并氮杂卓-6-酮甲状旁腺激素受体 1 拮抗剂。
Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1.
机构信息
End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
出版信息
Bioorg Med Chem. 2020 Jun 1;28(11):115524. doi: 10.1016/j.bmc.2020.115524. Epub 2020 Apr 22.
Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.
对先前在我们实验室合成的 1,4-苯并二氮杂卓-2-酮类甲状旁腺素受体 1（PTHR1）拮抗剂 5 进行结构修饰，得到化合物 10，其化学稳定性优于化合物 5。对先导化合物 10 进行连续优化，提高了其水溶解度、代谢稳定性和动物药代动力学特性，最终确定了 DS37571084（12）。我们的研究为发现新型口服生物可利用的 PTHR1 拮抗剂铺平了道路。
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