Rapid generation of novel benzoic acid-based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study
Rapid generation of novel benzoic acid-based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study
复制标题
快速生成新型苯甲酸基黄嘌呤衍生物作为高效、选择性和长效的 DPP-4 抑制剂：支架跳跃和前药研究
DOI：
10.1016/j.ejmech.2019.07.045
复制
发表时间：
2019-10-15
影响因子：
6.7
通讯作者：
Yao, Gongmei
中科院分区：
文献类型：
--
作者：
Li, Qing;Meng, Liuwei;Yao, Gongmei
通过使用从我们先前报道的骨架尿嘧啶到黄嘌呤（批准的药物利格列汀的骨架）的骨架跳跃策略，快速产生一系列并入苯甲酸部分的新型黄嘌呤衍生物2a-l。在围绕苯甲酸部分进行系统的构效关系（SAR）研究后，5种低皮摩尔效价范围的新型DPP-4抑制剂（IC 50 < 1 nM）和对各种DPP-4同系物的优异选择性，其中最好的化合物2f对DPP-4的IC 50值为0.1 nM，与先导化合物尿嘧啶1相比，其抑制活性提高了22倍，其活性是阿格列汀的45倍。选择2 e、2f、2 i和2k进行药代动力学评价，其中2f和2 i静脉给药后的药代动力学特征较好，但口服生物利用度较差。为了改善口服药代动力学特征，围绕2f和2 i进行前药设计方法。合成了2f和2 i的酯，并评价了其稳定性、毒性和药代动力学。化合物3e（化合物2f的甲酯）被鉴定为显示出良好的稳定性、低毒性和改善的口服生物利用度，在大鼠中与2f相比具有3倍高的血液浓度。以下体内评价显示3e提供持续48小时的药效学作用，并且以剂量依赖性方式稳健地改善正常ICR和db/db小鼠的葡萄糖耐量。慢性治疗研究表明，3e对2型糖尿病db/db小鼠的空腹血糖水平和糖耐量的有益作用比阿格列汀更明显。总体结果表明，化合物3e具有有效、安全和长效治疗T2 DM的潜力。(C)2019 Elsevier Masson SAS。All rights reserved.
A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC50 < 1 nM) and excellent selectivity against various DPP-4 homologues were identified, in which the best one, compound 2f, with the IC50 value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM. (C) 2019 Elsevier Masson SAS. All rights reserved.