RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345
RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345
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DOI：
10.1080/13543776.2017.1262350
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发表时间：
2017-01-01
影响因子：
6.6
通讯作者：
Gege, Christian
中科院分区：
文献类型：
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作者：
Gege, Christian
视黄酸受体相关孤儿核受体γ t （ROR γ t或RORc2）是初始促炎CD4(+) t细胞分化和t辅助-17 （t (H)17）细胞生成的关键转录因子。抑制ROR γ t活性被认为对多种炎症和自身免疫性疾病有益。最近，Vitae Pharmaceuticals（即将被Allergan收购）报告了一项针对银屑病患者的ROR γ t抑制剂VTP-43742的2a期临床试验的阳性结果。据报道，该化合物在短短四周内显示出明确的疗效信号，未观察到与药物相关的心脏异常；然而，在700mg剂量组中，有4例患者观察到可逆性转氨酶升高，这促使该公司取消了最初计划的第三次更高剂量VTP-43742的试验。在Vitae Pharmaceuticals的最新专利申请WO2016061160和US20160122345中，公开了临床候选药物vvp -43742（涵盖于WO2015116904）的潜在二氢吡咯吡啶备用化合物。针对最近宣布的ROR γ t备份分子VTP-45489，讨论了新化合物的改进并阐明了它们的潜在影响。
Retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t or RORc2) is a key transcription factor for the differentiation of naive proinflammatory CD4(+) T cells and the production of T helper-17 (T(H)17) cells. Inhibiting ROR gamma t activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently Vitae Pharmaceuticals (to be acquired by Allergan) reported positive top-line results from a Phase 2a clinical trial of ROR gamma t inhibitor VTP-43742 in psoriatic patients. The compound was reported to demonstrate a clear signal of efficacy over a short four-week period and no drug-related cardiac abnormalities were observed; however, in the 700mg dose group reversible transaminase elevations were observed in four patients, which prompted the company to cancel testing VTP-43742 at a initially planned third, higher dose. In Vitae Pharmaceuticals latest patent applications, WO2016061160 and US20160122345, potential dihydropyrrolopyridine back-up compounds of clinical candidate VTP-43742 (covered in WO2015116904) are disclosed. In light of the recently announced ROR gamma t back-up molecule VTP-45489, the improvements of the new compounds are discussed and their potential impact is elucidated.