阿佩林
兴奋剂
化学
药理学
广告
受体
体内
效力
内科学
内分泌学
脂肪变性
药代动力学
生物化学
体外
医学
生物
生物技术
作者
Sanju Narayanan,Shaobin Wang,Vineetha Vasukuttan,Ravi Kumar Vyas Devambatla,Donghua Dai,Chunyang Jin,Rodney W. Snyder,Lucas Laudermilk,Scott P. Runyon,Rangan Maitra
标识
DOI:10.1021/acs.jmedchem.0c01448
摘要
Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound 13 with favorable agonist potency (cAMPi EC50 = 162 nM), human liver microsome stability (T1/2 = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.
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