分类: 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间: 2017-11-17
摘要: The structural superposition of DPP-IV complex with Alogliptin and Linagliptin displayed a similar binding mode. The butynyl of Linagliptin and cyanobenzyl of Alogliptin occupy the S1 pocket which therefore could be mutually switched. Thus a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor 61. Though it did not exhibit desired activity (IC50= 0.2 礛), the butynyl compound acts as a lead compound triggered a following structural optimization. A novel series of potent DPP-IV inhibitors represented by compound 77 (IC50= 0.36 nM) were obtained with a robust pharmacokinetic profile and better in vitro and in vivo efficacy than Alogliptin.
分类: 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间: 2017-11-17
摘要: A new chemical class of potent DPP-IV inhibitors has been structurally derived from our recently disclosed pyrrolopyrimidine scaffold by replacing cyanobenzyl with butynyl group. Systematic variations and structure-activity relationship studies have been conducted on the starting hit 51 (IC50= 0.46 μM). Consequently, compound 78 (IC50= 1.55 nM) was identified to be a potent, selective, and orally available lead, worth further evaluations and optimizations.
分类: 生物学 >> 生态学 提交时间: 2017-11-17
摘要: Drug compliance is critical for the patients with chronic diseases like diabetes. In our continuous effort to find better glucose lowering agents, an exploration for long-acting DPP-4 inhibitor had been launched. Based on our previous reported compound 111 bearing a pyrrolopyrimidine scaffold, lead compound 114 (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) was rapidly determined with the pharmacokinetic superiority. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which the β-substitution gave a better DPP-4 affinity. In depth evaluation on β position of pyrrole ring brought up with highly potent compound 124 (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated a similar or even slightly better sustained DPP-4 inhibition of compound 114 and 124 compared with the first marketed once-weekly drug Trelagliptin in this category, indicating that improvement of DPP-4 inhibitory activity or pharmacokinetic profile might be both feasible ways to rapid generation of long-acting DPP-4 inhibitors.
分类: 生物学 >> 生态学 提交时间: 2017-11-17
摘要: Followed pharmacological evaluation exposed an extensive hepatic first pass effect within our recently disclosed DPP-IV inhibitors bearing thienopyrimidine scaffold. Through scaffold replacement with pyrrolopyrimidine, compound 1a had substantially improved the metabolic stability (from 6.6% to 65.07%), yet with severely poor absorptive property. Further modification by incorporation with varied substituents and structure conversion yielded both permeable and metabolic stable compounds. The whole pharmacokinetic- property based optimization had succeeded in balancing overall properties and resulted in the compound 1j, that with excellent efficacy to be a potential anti-diabetic candidate.