Department of Biological Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, USA.
Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, USA.
Chem Biol Drug Des. 2022 Jun;99(6):857-867. doi: 10.1111/cbdd.14039. Epub 2022 Apr 4.
We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5 μM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs.
我们报告了两种新型基于 2-氨基噻吩的胰高血糖素样肽 1 受体 (GLP-1R) 小分子正变构调节剂 (PAM) 的发现，可用于治疗 2 型糖尿病。其中一种化学型（S-1）的分子量为 239g/mol，是所有报道的 GLP-1R PAM 中分子量最小的分子。在细胞测定中，S-1 与 GLP-1 肽结合后，以剂量依赖的方式增加 GLP-1R 活性。当与血管活性肠肽受体 1 (VIPR1) 的肽激动剂结合时，S-1 对 VIPR1 （另一种存在于同一 HEK293-CREB 细胞系中的 B 类 GPCR）没有特异性活性。胰岛素分泌研究发现，S-1 与 GLP-1 结合后，在 5μM 时胰岛素分泌增加了 1.5 倍。在一项机制研究中，有证据表明 S-1 与 GLP-1 的协同作用可能部分归因于基于 CREB 的磷酸化作用的增强。鉴于这些化学型的良好特性，本文的工作表明，2-氨基噻吩衍生物是一类新型的有前途的 GLP-1R PAM。
