The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119
The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119
复制标题
黄嘌呤衍生物的优化导致 HBK001 盐酸盐作为靶向 DPP-IV 和 GPR119 的有效双配体
DOI：
10.1016/j.ejmech.2019.112017
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发表时间：
2020-02-15
影响因子：
6.7
通讯作者：
Huang, Haihong
中科院分区：
文献类型：
--
作者：
Li, Gang;Meng, Bingxu;Huang, Haihong
通过成环策略，发现了一系列由hit 20 i衍生的末端侧链修饰的黄嘌呤化合物。对疏水侧链中具有刚性杂环的化合物进行系统优化，得到新的先导化合物HBK 001（21 h），其具有改善的DPP-IV抑制和适度的体外GPR 119激动活性。作为进一步研究PK和PD特征的持续工作，以克为单位合成21 h及其盐酸盐（22），并在ICR小鼠中进行ADME/T和口服葡萄糖耐量试验（OGTT）评价。化合物22与其游离碱21 h相比显示出改善的生物利用度和降血糖作用，这可能归因于其改善的溶解性和渗透性。对化合物22的初步毒性研究表明，其mini-Ames试验结果为阴性，小鼠急性毒性LD_（50）大于1.5 g/kg，对hERG通道有中度抑制作用，IC_（50）为4.9 μ M，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配体靶向DPP-IV和GPR 119治疗糖尿病的药物。(C)2020 Elsevier Masson SAS。All rights reserved.
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 LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 mu M 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. (C) 2020 Elsevier Masson SAS. All rights reserved.