Identification of novel GPR81 agonist lead series for target biology evaluation.,Bioorganic & Medicinal Chemistry Letters

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Identification of novel GPR81 agonist lead series for target biology evaluation.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.bmcl.2020.126953
Öjvind Davidsson ₁ , Kristina Nilsson ₁ , Jonas Brånalt ₁ , Terese Andersson ₂ , Kristina Berggren ₃ , Yantao Chen ₁ , Ola Fjellström ₄ , Henrik Gradén ₁ , Linda Gustafsson ₁ , Nils-Olov Hermansson ₅ , Frank Jansen ₆ , Petra Johannesson ₇ , Bengt Ohlsson ₁ , Christian Tyrchan ₃ , Annika Wellner ₃ , Eric Wellner ₁ , Maria Ölwegård-Halvarsson ₁

Affiliation

CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Product Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; RIA Medicinal Chemistry, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Global Patient Safety CVRM, Chief Medical Office, AstraZeneca R&D, Gothenburg, Sweden.

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.

中文翻译：

鉴定用于目标生物学评估的新型GPR81激动剂前导系列。

GPR81是一种新型药物靶标，与葡萄糖和脂质代谢的控制有关。缺乏适用于体内研究的强效GPR81调节剂，限制了该乳酸传感受体的药理学表征。我们进行了高通量筛选（HTS），并确定了一个GPR81激动剂化学系列，其中包含一个中央酰基尿素支架接头。在SAR探索过程中，又开发了两个新系列，其中一个包含环状酰基脲生物等位基因，另一个包含中央酰胺键。这三个系列提供了适用于体内研究的不同选择性和理化性质。

更新日期：2020-01-07

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