Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29.
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
在此，我们报告了我们的先导优化工作，以确定有效、选择性和可口服的 TYK2 抑制剂，从先导分子 3 开始。我们使用基于结构的设计发现了 2,6-二氯-4-氰基苯基和（1R,2R）-2-氟环丙基酰胺修饰，与 3 相比，每个修饰都显示出提高的 TYK2 效力和 JAK1 和 JAK2 选择性。进一步的优化最终导致了化合物 37 的出现，它显示出良好的 TYK2 酶和白细胞介素-12（IL-12）细胞效力，以及可接受的细胞 JAK1 和 JAK2 选择性和在小鼠中的优异口服暴露。当在小鼠白细胞介素-12（IL-12）PK/PD 模型中进行测试时，化合物 37 显示出细胞因子干扰素-γ（IFNγ）的统计学显著下调，表明 TYK2 激酶活性的选择性抑制可能足以阻断体内的 IL-12 途径。
