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Identification of novel GPR81 agonist lead series for target biology evaluation
Institution:1. Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495 009, Chhattisgarh, India;2. Department of Zoology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India;1. CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China;2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China;3. Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, School of Medicine, Stanford University, Stanford, CA 94305-5484, USA;1. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China;2. BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China;1. Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada;2. Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada;3. Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada;1. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China;2. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China;3. University of Chinese Academy of Sciences, Beijing 100049, PR China;4. Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Jiangsu 210009, PR China;5. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China
Abstract: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.
Keywords:GPCR  GPR81  GPR109A  GHSR1a  Lipolysis  HTS
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