Schlegel Jonathan G, Tahoun Mariam, Seidinger Alexander, Voss Jan H, Kuschak Markus, Kehraus Stefan, Schneider Marion, Matthey Michaela, Fleischmann Bernd K, König Gabriele M, Wenzel Daniela, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Department of Systems Physiology, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany.
ACS Pharmacol Transl Sci. 2021 Feb 19;4(2):888-897. doi: 10.1021/acsptsci.1c00021. eCollection 2021 Apr 9.
Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, G protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such as asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent selective inhibitors of the Gq subfamily of G proteins. FR and YM differ in two positions, FR being more lipophilic than YM. Both compounds are utilized as pharmacological tools to block Gq proteins in vitro and in vivo. However, no detailed characterization of FR and YM has been performed, which is a prerequisite for the compounds' translation into clinical application. Here, we performed a thorough study of both compounds' physicochemical, pharmacokinetic, and pharmacological properties. Chemical stability was high across a large range of pH values, with FR being somewhat more stable than YM. Oral bioavailability and brain penetration of both depsipeptides were low. FR showed lower plasma protein binding and was metabolized significantly faster than YM by human and mouse liver microsomes. FR accumulated in lung after chronic intratracheal or intraperitoneal application, while YM was more distributed to other organs. Most strikingly, the previously observed longer residence time of FR resulted in a significantly prolonged pharmacologic effect as compared to YM in a methacholine-induced bronchoconstriction mouse model. These results prove that changes within a molecule which seem marginal compared to its structural complexity can lead to crucial pharmacological differences.
鸟嘌呤核苷酸结合蛋白（G蛋白）将G蛋白偶联受体（GPCR）接收到的细胞外信号转导至细胞内信号级联反应。虽然GPCR是最大的一类药物靶点，但G蛋白抑制作用直到最近才被认为是治疗哮喘、炎症和癌症等复杂疾病的一种新策略。结构相似的大环缩肽FR900359（FR）和YM-254890（YM）是G蛋白Gq亚家族的强效选择性抑制剂。FR和YM在两个位置上有所不同，FR比YM更具亲脂性。这两种化合物都被用作药理学工具，在体外和体内阻断Gq蛋白。然而，尚未对FR和YM进行详细的特性描述，而这是将这些化合物转化为临床应用的先决条件。在此，我们对这两种化合物的物理化学、药代动力学和药理学特性进行了全面研究。在很大的pH值范围内，化学稳定性都很高，FR比YM稍微更稳定一些。这两种缩肽的口服生物利用度和脑渗透率都很低。FR显示出较低的血浆蛋白结合率，并且在人和小鼠肝微粒体中比YM代谢得明显更快。在慢性气管内或腹腔内给药后，FR在肺中蓄积，而YM则更多地分布到其他器官。最引人注目的是，在甲胆碱诱导的支气管收缩小鼠模型中，与YM相比，先前观察到的FR更长的停留时间导致了显著延长的药理作用。这些结果证明，与分子的结构复杂性相比看似微不足道的分子内部变化可能会导致关键的药理学差异。
