R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem. 2018 Oct 1;26(18):5099-5117. doi: 10.1016/j.bmc.2018.09.005. Epub 2018 Sep 8.
Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients.
为避免肝毒性，尝试降低先前合成的化合物（II）的亲脂性。用 2-吡啶取代左手边的苯导致活性显著降低。由于较差的膜通透性是体外活性差的原因，因此检查了亲脂性的调整，从而发现了二甲基吡啶衍生物（I，DS-6930）。在临床前研究中，DS-6930 表现出高 PPARγ 激动剂活性，具有强大的血糖降低作用。DS-6930 在体内毒理学评价中保持了减少的与 PPARγ 相关的不良反应，并且没有肝毒性。辅助因子募集试验表明，几种辅助因子，如 RIP140 和 PGC1，被显著募集，而几种规范因子不受影响。这种选择性辅助因子募集是由于 DS-6930 的独特结合模式引起的。钙盐 DS-6930b 有望成为一种有效的胰岛素增敏剂，不会引起水肿，可在 T2DM 患者中进行临床评估。
