Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer.
Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer.
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DOI：
10.1002/ddr.21926
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发表时间：
2022-06
影响因子：
3.8
通讯作者：
Arnold, Leggy A.
中科院分区：
文献类型：
--
作者：
Roni, M. S. Rashid;Zahn, Nicolas M.;Yocum, Gene T.;Webb, Daniel A.;Mian, Md Yeunus;Meyer, Michelle J.;Tylek, Anika S.;Cook, James M.;Emala, Charles W.;Stafford, Douglas C.;Arnold, Leggy A.
MIDD0301正在开发为一种口服药物，用于松弛哮喘患者的呼吸道平滑肌和减少肺部炎症。我们报道了MIDD0301及其S异构体(MIDD0301S)的比较研究，发现这两个化合物对大鼠脑内表达的GABAAR具有相当的亲和力，对S和R对映体的IC50值分别为25.1nM和26.3nM。这两个化合物都松弛P物质在30分钟内收缩的气道平滑肌，两个对映体都没有显示出与48个受体的非靶点亲和力。在两种小鼠的支气管收缩模型中，两种对映体都通过雾化吸入和口服剂量降低了气道高反应性(AHR)。在对乙酰甲胆碱引起的支气管收缩非常敏感的A/J小鼠中，我们观察到10.8 mg/kg MIDD0301和15 mg/kg MIDD0301S降低了AHR。口服100 mg/kg/d，连续3天服用上述两种对映体均足以降低AHR。在干扰素-γ和脂多糖诱导的严重气道炎症模型中，雾化给药和口服给药均可使对映体的AHR降低7.2 mg/kg和100 mg/kg。MIDD0301和MIDD0301S未发生I期代谢。两个化合物都观察到了葡萄糖醛酸化作用，而只有MIDD0301在肾脏微生物体存在的情况下形成了相应的葡萄糖苷。药代动力学分析表明，葡萄糖醛酸苷是主要代谢物，其浓度是母体化合物的20倍以上。MIDD0301葡萄糖醛酸苷和MIDD0301牛磺酸结合GABAARs，虽然比MIDD0301弱10倍。在小鼠血中，仅观察到MIDD0301的牛磺酸加合物。总体而言，这两种化合物表现出类似的受体结合和药效学特性，但在代谢方面存在细微差异，MIDD0301S的口服利用度和血液浓度更高。
MIDD0301 is being developed as an oral drug to relax airway smooth muscle and reduce lung inflammation in asthma. We report a comparative study of MIDD0301 and its S isomer (MIDD0301S) and found that the compounds have equivalent affinity for GABAAR expressed in rat brain, with IC50 values of 25.1 nM and 26.3 nM for the S and R enantiomers, respectively. Both compounds relaxed substance P contracted airway smooth muscle within 30 min and neither enantiomer revealed affinity to 48 receptors in an off-target screen. Both enantiomers reduced airway hyperresponsiveness (AHR) with nebulized and oral dosing in two mouse models of bronchoconstriction. In A/J mice, which are very sensitive to methacholine-induced bronchoconstriction, we observed reduction of AHR at 10.8 mg/kg MIDD0301 and 15 mg/kg MIDD0301S. Using oral administration, 100 mg/kg/day for three days of either enantiomer was sufficient to reduce AHR. In a model of severe airway inflammation induced by INFγ and LPS, we observed reduction of AHR at 7.2 mg/kg for both enantiomers using nebulized administration and at 100 mg/kg for oral administration. MIDD0301 and MIDD0301S did not undergo phase I metabolism. Glucuronidation was observed for both compounds, whereas only MIDD0301 formed the corresponding glucoside in the presence of kidney microsomes. Pharmacokinetic analysis identified glucuronides as the major metabolite with concentrations up to 20-fold more than the parent compound. MIDD0301 glucuronide and MIDD0301 taurine bind GABAARs, although 10-fold weaker than MIDD0301. In mouse blood, the taurine adduct was only observed for MIDD0301. Overall, both compounds exhibited similar receptor binding and pharmacodynamic properties with subtle differences in metabolism and greater oral availability and blood concentrations of MIDD0301S.
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影响因子：
4.9
作者：
Forkuo GS;Guthrie ML;Yuan NY;Nieman AN;Kodali R;Jahan R;Stephen MR;Yocum GT;Treven M;Poe MM;Li G;Yu OB;Hartzler BD;Zahn NM;Ernst M;Emala CW;Stafford DC;Cook JM;Arnold LA
通讯作者：
Arnold LA
影响因子：
4.9
作者：
Forkuo GS;Nieman AN;Yuan NY;Kodali R;Yu OB;Zahn NM;Jahan R;Li G;Stephen MR;Guthrie ML;Poe MM;Hartzler BD;Harris TW;Yocum GT;Emala CW;Steeber DA;Stafford DC;Cook JM;Arnold LA
通讯作者：
Arnold LA
影响因子：
4.9
作者：
Forkuo GS;Nieman AN;Kodali R;Zahn NM;Li G;Rashid Roni MS;Stephen MR;Harris TW;Jahan R;Guthrie ML;Yu OB;Fisher JL;Yocum GT;Emala CW;Steeber DA;Stafford DC;Cook JM;Arnold LA
通讯作者：
Arnold LA
DOI：
10.1152/ajplung.00107.2014
发表时间：
2015-05-01
影响因子：
4.9
作者：
Gallos, George;Yocum, Gene T.;Emala, Charles W., Sr.
通讯作者：
Emala, Charles W., Sr.
影响因子：
7.3
作者：
IM, WB;PREGENZER, JF;THOMSEN, DR
通讯作者：
THOMSEN, DR