Cayman Chemical Company, Inc., 1180 East Ellsworth Rd., Ann Arbor, MI, USA.
Cayman Chemical Company, Inc., 1180 East Ellsworth Rd., Ann Arbor, MI, USA.
Bioorg Med Chem Lett. 2021 Feb 15;34:127759. doi: 10.1016/j.bmcl.2020.127759. Epub 2020 Dec 29.
In seeking novel and potent small molecule hematopoietic prostaglandin D synthase (H-PGDS) inhibitors as potential therapies for PGD-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole "linker" between the pyrimidine or pyridine "core" ring and the "tail" ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.
在寻找新型、有效的小分子造血前列腺素 D 合酶 (H-PGDS) 抑制剂作为治疗 PGD 介导的疾病和病症的潜在疗法时，我们探索了一系列线性排列的多个芳基/杂芳基环组成的化合物。每个化合物在嘧啶或吡啶“核心”环和“尾部”环系统之间都有酰胺或咪唑“连接物”。我们通过荧光偏振结合测定法、热位移测定法、谷胱甘肽 S-转移酶抑制测定法和基于细胞的测定法（测量抑制 LPS 诱导的 PGD 刺激）合成并筛选了二十种类似物。与没有 GSH 的相同测定相比，在存在谷胱甘肽 (GSH) 的情况下，酰胺类似物在热位移测定中显示出十倍的更大位移。咪唑类似物在两种测定条件之间没有产生热位移的显著变化，这表明酰胺连接物在合酶-GSH-抑制剂复合物中可能具有稳定作用。咪唑类似物 23（KMN-010034）在体外测定中表现出优异的效力，并且在人肝微粒体和豚鼠肝微粒体中都具有良好的体外代谢稳定性。
