Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Escalating Oral Doses of LY2881835 in Healthy Subjects and Patients With Type 2 Diabetes Mellitus

This will be the first study in which LY2881835 is given to humans in order to evaluate the safety and any side effects of LY2881835 in humans as well as how long LY2881835 stays in the body and its effect on blood sugar levels.
The study consists of two parts. In part A, healthy subjects will participate and in part B, patients with type 2 Diabetes Mellitus (T2DM) will participate.

开始日期2011-05-24

申办/合作机构

Eli Lilly & Co.

100 项与 LY-2881835 相关的临床结果

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100 项与 LY-2881835 相关的转化医学

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100 项与 LY-2881835 相关的专利（医药）

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项与 LY-2881835 相关的文献（医药）

2019-05-01·Chemical Biology & Drug Design4区 · 医学

Design, synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1

4区 · 医学

Article

作者: Tang, Chunlei ; Gu, Enke ; Yang, Jiaju ; Feng, Bainian ; Shen, Daoming ; Yan, Ting

AbstractFree fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK‐875, AMG‐837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC50 values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK‐875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose‐lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.

2018-05-01·European Journal of Medicinal Chemistry1区 · 医学

Design, synthesis and structure−activity relationship studies of GPR40 agonists containing amide linker

1区 · 医学

Article

作者: Wang, Kai ; Shen, Jianhua ; Chen, Tingting ; Ning, Mengmeng ; Ye, Yangliang ; Leng, Ying

Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.

2017-02-01·European Journal of Medicinal Chemistry1区 · 医学

Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835

1区 · 医学

Article

作者: Zhurilo, Nikolay ; Lukin, Alexey ; Krasavin, Mikhail ; Golovanov, Aleksei ; Zahanich, Ihor ; Bagnyukova, Daria ; Moore, Daniel ; Tikhonova, Irina G ; Zozulya, Sergey

A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC₅₀ = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.

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