RO4597014的鉴定，一种正在临床研究用于治疗2型糖尿病的葡萄糖激酶激活剂。
Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.
作者信息
Qian Yimin, Corbett Wendy L, Berthel Steven J, Choi Duk Soon, Dvorozniak Mark T, Geng Wanping, Gillespie Paul, Guertin Kevin R, Haynes Nancy-Ellen, Kester Robert F, Mennona Francis A, Moore David, Racha Jagdish, Radinov Roumen, Sarabu Ramakanth, Scott Nathan R, Grimsby Joseph, Mallalieu Navita L
机构信息
Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
出版信息
ACS Med Chem Lett. 2013 Mar 7;4(4):414-8. doi: 10.1021/ml400027y. eCollection 2013 Apr 11.
Abstract
To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.
摘要
为解决与我们早期临床化合物2相关的代谢物氧化还原循环问题，我们对先导分子1进行了先导优化。化合物4显示出改善的亲脂性配体效率，并在饮食诱导的肥胖小鼠中表现出强大的降糖作用，且在预测性临床前药物安全性研究中没有不良影响。因此，它被选为临床候选药物，并在2型糖尿病患者中进一步研究。临床数据表明没有代谢物循环的证据，这与代谢的临床前分析结果一致。
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