2-aryloxy-4-alkylaminopyridines: Discovery of novel corticotropin-releasing factor 1 antagonists
2-aryloxy-4-alkylaminopyridines: Discovery of novel corticotropin-releasing factor 1 antagonists
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DOI：
10.1021/jm070579c
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发表时间：
2008-03-13
影响因子：
7.3
通讯作者：
Schulz, David W.
中科院分区：
文献类型：
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作者：
Chen, Yuhpyng L.;Obach, R. Scott;Schulz, David W.
一种具有口服活性的促肾上腺皮质激素释放因子1（CRF（1））拮抗剂1的临床候选药物在犬和人中经口给药后显示出显著的正性食物效应。解决食物效应问题的努力使我们探索和发现系列2中的化合物作为口服活性CRF（1）受体拮抗剂，其中一些化合物显示出改善的物理化学性质，同时保留所需的药理学性质。选择化合物3a（CP-376395）进行进一步开发，这不仅是因为其减少了食物效应，而且还因为其在CNS模型中具有更大的功效。将化合物3a推进到临床。代表性的潜在候选物的合成和它们的体外、离体和体内数据被描述。
An orally active clinical candidate of corticotropin-releasing factor 1 (CRF(1)) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF(1) receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.