吡咯并[1,2 - b]哒嗪 - 3 - 甲酰胺作为Janus激酶（JAK）抑制剂的发现。
Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.
作者信息
Duan James J-W, Lu Zhonghui, Jiang Bin, Yang Bingwei V, Doweyko Lidia M, Nirschl David S, Haque Lauren E, Lin Shuqun, Brown Gregory, Hynes John, Tokarski John S, Sack John S, Khan Javed, Lippy Jonathan S, Zhang Rosemary F, Pitt Sidney, Shen Guoxiang, Pitts William J, Carter Percy H, Barrish Joel C, Nadler Steven G, Salter-Cid Luisa M, McKinnon Murray, Fura Aberra, Schieven Gary L, Wrobleski Stephen T
机构信息
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
出版信息
Bioorg Med Chem Lett. 2014 Dec 15;24(24):5721-5726. doi: 10.1016/j.bmcl.2014.10.061. Epub 2014 Oct 24.
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
利用合理设计的吡咯并[1,2 - b]哒嗪 - 3 - 甲酰胺支架发现了一类新型的 Janus 激酶（JAK）抑制剂。初步研究确定（R）-（2,2 - 二甲基环戊基）胺是吡咯并哒嗪核心（3b）上的优选 C4 取代基。在环戊烷环的 3 位引入氨基得到了一系列 JAK3 抑制剂（4g - 4j），这些抑制剂在 IL2 诱导的全血试验中能有效抑制 IFNγ 的产生，并且相对于 JAK2 对 JAK3 - JAK1 途径表现出高功能选择性。进一步的修饰导致发现了一种口服生物可利用的（2 - 氟 - 2 - 甲基环戊基）氨基类似物 5g，它是 JAK3 和 TYK2 的纳摩尔级抑制剂，相对于 JAK2 对 JAK3 - JAK1 途径具有功能选择性，并且在人全血试验中具有活性。
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