GPR103 Antagonists Demonstrating Anorexigenic Activity in Vivo: Design and Development of Pyrrolo[2,3-c]pyridines That Mimic the C-Terminal Arg-Phe Motif of QRFP26

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• 作者：Jennie Georgsson ; Fredrik Bergstr枚m ; Anneli Nordqvist ; Martin J. Watson ; Charles D. Blundell ; Magnus J. Johansson ; Annika U. Petersson ; Zhong-Qing Yuan ; Yiqun Zhou ; Lisbeth Kristensson ; Dorota Kakol-Palm ; Christian Tyrchan ; Eric Wellner ; Udo Bauer ; Peter Brodin ; Anette Svensson Henriksson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5935-5948
• 全文大小：482K
• ISSN：1520-4804

文摘

GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development. In a preclinical obesity model measuring food intake, the anorexigenic effect of a pyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated. In addition, the dynamic 3D solution structure of the C-terminal heptapeptide of the endogenous agonist QRFP26_(20鈥?6) was determined using NMR. The synthetic pyrrolo[2,3-c]pyridine antagonists were compared to this experimental structure, which displayed a possible overlay of pharmacophore features supportive for further design of GPR103 antagonists.