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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 8. Pharmacological Optimization of Orally Bioavailable 2-Pyridone-Containing Peptidomimetics
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Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 8. Pharmacological Optimization of Orally Bioavailable 2-Pyridone-Containing Peptidomimetics

机译：基于结构的不可逆人类鼻病毒3C蛋白酶抑制剂的设计，合成和生物学评估。 8.口服可生物利用的含2-吡啶酮的拟肽的药理优化

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摘要

The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an α, β-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P_2 substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an α, β-unsaturated ethyl ester fragment and either an ethyl or propargyl P_2 moiety displayed the most promising combination of 3C enzyme inhibition (k_(obs)/[I] 170000-223000 M~(-1)s~(-1)), antiviral activity (EC_(50) = 0.047-0.058 μM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 μM; 7 h CM-monkey plasma levels = 0.057-0.896 μM).
机译：描述了对比格犬或CM-猴子口服给药后，各种含2-吡啶酮的人鼻病毒（HRV）3C蛋白酶（3CP）抑制剂的药代动力学性能的优化。这项工作中描述的分子由含2-吡啶酮的拟肽结合决定簇和与3C酶的活性位点半胱氨酸残基形成不可逆的共价加合物的α，β-不饱和酯Michael受体部分组成。这些化合物中所含酯的修饰以及抑制剂的拟肽部分中存在的P_2取代基的改变均已详述。描述了几种抑制剂在狗和猴子中的药代动力学（口服给药后7 h血浆浓度），以及它们的人血浆稳定性，与人，狗和猴子微粒体和肝细胞孵育的稳定性，Caco-2渗透性和水溶解度。包含α，β-不饱和乙酯片段和乙基或炔丙基P_2部分的化合物表现出最有希望的3C酶抑制组合（k_（obs）/ [I] 170000-223000 M〜（-1）s〜（- 1）），抗病毒活性（EC_（50）= 0.047-0.058μM，平均值vs七种HRV血清型）以及口服后的药代动力学（狗7小时血浆水平= 0.248-0.682μM; CM-猴子7小时血浆水平= 0.057） -0.896μM）。

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