Hamilton Gregory L, Chen Huifen, Deshmukh Gauri, Eigenbrot Charles, Fong Rina, Johnson Adam, Kohli Pawan Bir, Lupardus Patrick J, Liederer Bianca M, Ramaswamy Sreemathy, Wang Haowei, Wang Jian, Xu Zhaowu, Zhu Yunliang, Vucic Domagoj, Patel Snahel
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Bioorg Med Chem Lett. 2019 Jun 15;29(12):1497-1501. doi: 10.1016/j.bmcl.2019.04.014. Epub 2019 Apr 11.
Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.
受体相互作用蛋白激酶1（RIPK1）是细胞坏死性凋亡途径的关键组成部分，已成为一个重要的治疗靶点。RIPK1的药理抑制或基因失活在多种疾病的动物模型中显示出前景，这些疾病包括急性缺血性疾病、慢性炎症和神经退行性疾病。我们在此展示了一类RIPK1抑制剂，其特点是缺乏大多数文献报道的抑制剂中存在的亲脂性芳香基团，该基团通常占据蛋白质活性位点的疏水后口袋。尽管没有许多已知RIPK1抑制剂的这一普遍特征，但我们能够获得在大鼠中具有良好效力、激酶选择性和药代动力学性质的化合物。使用亲脂性但代谢稳定的五氟乙基对于平衡优化类似物的效力和性质至关重要。
