SYL927 and SYL930, two aminopropanediol analogues, are novel Sphingosine-1-phosphate receptor 1 (S1P₁) modulators with higher selectivity and pharmacological activity compared with FTY720. Although the immunosuppressive activity of SYLs has been well demonstrated, information regarding the metabolic fates of the two chemicals is limited except for the CYP-catalyzed hydroxylation of SYL930. In this study, the biotransformation schemes of the two promising chemicals were investigated and compared using liver microsomes, S9 fractions and recombinant enzymes, and relevant molecular mechanism was primarily demonstrated by ligand-enzyme docking analysis (CDOCKER). As a result, the hydroxylation at alkyl chain on oxazole ring by the action of CYPs was found for both SYLs in vivo. The SULT-catalyzed sulfonation of the hydroxide was observed for SYL927 while the ADH/ALDH-catalyzed oxidation was only discovered for SYL930. The docking analysis suggested that specific non-covalent forces and/or bonding conformations of the hydroxides with biomacromolecules might be involved in the disparate metabolism of SYLs. Exploring the metabolic characteristics will help clarify the substance base for efficacy and safety of the two drugs. The uncovered structure-metabolism relationship in this study may provide an implication for the design and optimization for other S1P modulators.

2019-02-01·Die Pharmazie4区 · 医学

The involvement of blood cells in the phosphorylation of the selective sphingosine-1-phosphate receptor 1 agonist SYL-927.

4区 · 医学

Article

作者: Yang, Shy ; Li, Yan ; Hu, Jin-Ping

SYL-927 is a selective sphingosine-1-phosphate receptor 1 (S1P₁) agonist for autoimmune diseases. It undergoes phosphorylation to the active SYL-927-P in vivo, which activates S1P₁ on lymphocytes, causing lymphopenia by retention of lymphocytes in the lymph nodes. The aim of this study was to identify the involvement of blood cells in the phosphorylation of SYL-927. In addition, pharmacokinetics of SYL-927 and SYL-927-P in blood and plasma were compared in rats. The results demonstrated that SYL-927 can be converted to SYL-927-P in rat blood, but not in rat plasma. However, both rat blood and plasma are capable of dephosphorylating SYL-927-P to SYL-927. SYL-927-P generation and release were observed after incubating SYL-927 with rat and human erythrocytes and platelets. The addition of sphingosine kinases (SPHKs) inhibitors N,N-dimethylsphingosine (DMS) and FTY720 significantly inhibited SYL-927-P generation, indicating the involvement of SPHKs. In addition, SYL-927 and SYL-927-P levels in blood were significantly higher than those in plasma after oral administration of SYL-927 in rats, suggesting the blood cells for the production of SYL-927-P. In summary, the blood cells such as erythrocytes and platelets contribute to the generation and release of SYL-927-P, which is important for maintaining plasma active phosphate levels for prolonged effects.

2018-11-01·Biopharmaceutics & Drug Disposition4区 · 医学

CYP2J2 is the major enzyme in human liver microsomes responsible for hydroxylation of SYL‐927, a novel and selective sphingosine 1‐phosphate receptor 1 (S1P₁) agonist

4区 · 医学

Article

作者: Yang, Shu ; Hu, Jinping ; Li, Yan ; Zhao, Zhigang

AbstractSYL‐927, a novel and selective S1P1 agonist, is transferred to its active phosphate for the regulation of lymphocyte recirculation. This in vitro metabolism study is to elucidate the P450‐mediated oxidation pathway of SYL‐927 in human liver microsomes (HLMs). The results demonstrated that the ω‐1 hydroxylated metabolite SYL‐927‐M was formed after incubation of SYL‐927 with HLMs. Recombinant human CYP1A1 and CYP2J2 can efficiently catalyse SYL‐927‐M formation, followed by markedly less substrate conversion with CYP1A2, CYP2C19 and CYP2D6. Inhibition studies with chemical inhibitors and antibodies suggested that arachidonic acid, the substrate of CYP2J2, and CYP2J2‐specific antibody effectively inhibited the formation of SYL‐927‐M in HLMs whereas no significant inhibition was observed with the inhibitors for CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, demonstrating that CYP2J2 was primarily responsible for the formation of SYL‐927‐M.

100 项与 SYL-927 相关的药物交易

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