Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)
Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)
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DOI：
10.1021/acs.jmedchem.8b00085
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发表时间：
2018-06-28
影响因子：
7.3
通讯作者：
Aronov, Alex M.
中科院分区：
文献类型：
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作者：
Come, Jon H.;Collier, Philip N.;Aronov, Alex M.
脂质激酶磷酸肌醇 3-激酶 γ (PI3K γ) 由于其在免疫调节和小胶质细胞激活中的作用，作为治疗多种自身免疫性疾病（包括多发性硬化症）的潜在靶点而受到关注。通过最大限度地减少氢键供体的数量，同时靶向与 PI3K γ 的 ATP 结合位点相邻的先前发现的选择性口袋，我们发现了一系列氮杂异吲哚酮作为 PI3K γ 的选择性脑渗透抑制剂。这最终导致了 16 的发现，这是一种口服生物可利用的化合物，对小鼠实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症的临床前模型）显示出疗效。
The lipid kinase phosphoinositide 3-kinase gamma (PI3K gamma) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3K gamma, we discovered a series of aza-isoindolinones as selective, brain penetrant inhibitors of PI3K gamma. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.