The discovery and potential of N-sulfonylated dipeptide VLA-4 antagonists.
The discovery and potential of N-sulfonylated dipeptide VLA-4 antagonists.
复制标题
N-磺酰化二肽 VLA-4 拮抗剂的发现和潜力。
DOI：
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发表时间：
2004
影响因子：
3.4
通讯作者：
W. Hagmann
中科院分区：
文献类型：
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作者：
W. Hagmann
通过对含有羧酸的组合文库的定向筛选，N-磺化二肽被鉴定为默克研究实验室VLA-4拮抗剂计划的先导。进一步优化，快速鉴定出比相关整合素α4beta7具有不同程度特异性的亚纳分子化合物。确定并处理了各种代谢性负债。然而，几乎所有这类化合物的药代动力学特性都是不可接受的。其他铅被发现具有明显的良好的口服生物利用度，但这些通常与非常高的血浆蛋白结合和效力丧失有关。大鼠高血浆清除率的机制被确认为有机酸转运体MRP-2。已确定的化合物不是MRP-2的底物，但它们仍然存在口服生物利用度低的问题。最后，战略的转变是确定适合吸入治疗的VLA-4拮抗剂，从而制备出具有特殊紧密结合特性的化合物。这些化合物在卵清蛋白致敏的嗜酸性粒细胞向肺转移的小鼠模型中优于BIO-1211。有一种特殊的化合物有非常长的折扣率，Kd<；或=2 PM我们实验室中结构和活性关系的演变以及改善效价和药动学的策略是本综述的主题。
Through a directed screening of a combinatorial library containing carboxylic acids, N-sulfonylated dipeptides were identified as leads in the Merck Research Laboratories VLA-4 antagonist program. Further optimization quickly identified subnanomolar compounds with varying degrees of specificity over the related integrin alpha4beta7. Various metabolic liabilities were identified and addressed. However, the pharmacokinetic properties of nearly all compounds in this class were unacceptable. Other leads were identified with apparent good oral bioavailability, but these were generally associated with very high plasma protein binding and a loss of potency. The mechanism of high plasma clearance was identified in the rat as the organic acid transporter, mrp-2. Compounds were identified that were not substrates of mrp-2, but they still suffered from poor oral bioavailability. Finally, a shift in strategy to identifying VLA-4 antagonists that would be suitable as candidates for inhalation therapy resulted in the preparation of compounds with exception tight binding properties. These compounds were superior to BIO-1211 in the ovalbumin-sensitized mouse model of eosinophil trafficking to the lung. One particular compound had an exceptionally long off-rate with a KD < or = 2 pM. The evolution of the structure activity relationships in our laboratories and strategies for improving potencies and pharmacokinetic profiles are the subject of this review.