State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China.
Eur J Med Chem. 2020 Feb 15;188:112017. doi: 10.1016/j.ejmech.2019.112017. Epub 2019 Dec 31.
A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
通过环化策略，从之前的命中化合物 20i 对末端侧链进行修饰，发现了一系列黄嘌呤类化合物。对疏水侧链中具有刚性杂环的化合物进行系统优化，得到了新的先导化合物 HBK001（21h），其对 DPP-IV 的抑制作用和对 GPR119 的激动作用均有所改善。作为进一步研究 PK 和 PD 特征的延续性工作，21h 及其盐酸盐（22）以克级规模合成，并在 ICR 小鼠上进行了 ADME/T 和口服葡萄糖耐量试验（OGTT）评估。与游离碱 21h 相比，化合物 22 显示出改善的生物利用度和体内降血糖作用，这可能归因于其改善的溶解度和通透性。化合物 22 的初步毒性研究表明，mini-Ames 试验结果为阴性，小鼠初步急性毒性 LD 在 1.5g/kg 以上，而其对 hERG 通道的抑制作用中等，IC 4.9μM，可能与其高亲脂性有关。这些发现将有助于未来设计更有效和更安全的双重配体，以靶向 DPP-IV 和 GPR119 治疗糖尿病。
