R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
R&D Division, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
J Med Chem. 2020 Sep 24;63(18):10204-10220. doi: 10.1021/acs.jmedchem.0c00259. Epub 2020 May 26.
A highly potent, selective Na1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives ( and ) led to the discovery of novel series of cycloalkane derivatives with high Na1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
一种高效、选择性的钠离子通道 1.7 型抑制剂 DS-1971a 已被发现。对磺酰胺衍生物（和）的左手苯环进行探索，导致了具有高体外钠离子通道 1.7 型抑制活性的新型环烷烃衍生物系列的发现。由于右手杂芳环影响 CYP3A4 的基于机制的抑制性，该部分的替换导致了 4-嘧啶基衍生物的产生。此外，通过这种修饰成功避免了 GSH 加合物的形成，这可能导致特发性药物毒性。进一步的优化导致了 DS-1971a 的发现。在临床前研究中，DS-1971a 表现出高度有效的选择性体外特征，在体内具有强大的疗效。DS-1971a 表现出有利的毒理学特征，这使得多达 600mg bid 或 400mg tid（1200mg/天）的剂量递增研究能够在健康男性中进行 14 天。DS-1971a 有望在外周神经性疼痛患者中发挥强效疗效，且具有良好的安全性特征。
