P38 MAP kinase inhibitors: evolution of imidazole-based and pyrido-pyrimidin-2-one lead classes.
P38 MAP kinase inhibitors: evolution of imidazole-based and pyrido-pyrimidin-2-one lead classes.
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P38 MAP 激酶抑制剂：基于咪唑和吡啶并-嘧啶-2-一先导类的演变。
DOI：
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发表时间：
2005
影响因子：
3.4
通讯作者：
J. Doherty
中科院分区：
文献类型：
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作者：
S. Natarajan;J. Doherty
SmithKline Beecham(SB)首次披露了三取代咪唑类药物分子(如用于抑制p38 MAP激酶的1)，这引发了默克公司和其他制药研究机构在这一领域的努力。虽然这类类似物对p38MAPK表现出良好的抑制性能，但它们的选择性不高，留有很大的改进空间。为了发现比典型的Sb化合物203580(1)具有更高选择性的新化合物，默克公司发现了以化合物18为代表的p38抑制剂的一个新亚类。尽管这种基准化合物是有效的、高度选择性的和口服有效的，但它在狗身上却背负着与化合物相关的不良反应，从而延缓了进一步的发育。1999年，Vertex制药公司披露了以临床候选药物VX-745(26)为代表的一类新的p38抑制剂。由于其与p38蛋白激酶活性部位结合的独特方式，该化合物显示出前所未有的选择性。受到VX-745[26]精致选择性特征的启发，默克公司启动了支架重新设计，结果发现了基于喹唑烷酮、嘧啶并嘧啶、嘧啶并嘧啶、喹诺酮和萘乙酮的p38抑制剂。
The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to discover newer compounds with improved selectivity over the prototypical SB compound 203580 (1), led to the discovery of a new sub-class of p38 inhibitors typified by compound 18 at Merck. Although this benchmark compound was potent, highly selective and orally efficacious it was burdened with compound related adverse effects in dogs that has delayed further development. In 1999, a new class of p38 inhibitors represented by clinical candidate VX-745 (26), was disclosed by Vertex Pharmaceuticals. This compound displayed unprecedented selectivity due to its unique mode of binding to the active site in p38 MAP kinase. Inspired by the exquisite selectivity profile of VX-745 [26] a scaffold re-design was initiated at Merck which resulted in the discovery of the quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone based p38 inhibitors.