气候变化领域集成服务门户(CCPortal): Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS

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DOI	10.1021/acsmedchemlett.8b00035
	Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
	Eidam, Hilary Schenck; Russell, John; Raha, Kaushik; DeMartino, Michael; Qin, Donghui; Guan, Huiping Amy; Zhang, Zhiliu; Zhen, Gong; Yu, Haiyu; Wu, Chengde; Pan, Yan; Joberty, Gerard; Zinn, Nico; Laquerre, Sylvie; Robinson, Sharon; White, Angela; Giddings, Amanda; Mohammadi, Ehsan; Greenwood-Van Meerveld, Beverly; Oliff, Allen; Kumar, Sanjay; Cheung, Mui
发表日期	2018
ISSN	1948-5875
起始页码	623
结束页码	628
卷号	9 期号:7
英文摘要	Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (IS, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC50 of 0.3 nM and is efficacious in vivo.
英文关键词	RET kinase; IBS; gut restricted; genotoxicity; AMES
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
来源期刊	ACS MEDICINAL CHEMISTRY LETTERS
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/158519
作者单位	Eidam, HS (corresponding author), GlaxoSmithKline, Virtual Proof Concept Discovery Performance Unit, King Of Prussia, PA 19406 USA.
推荐引用方式 GB/T 7714	Eidam, Hilary Schenck,Russell, John,Raha, Kaushik,et al. Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS[J],2018,9(7).
APA	Eidam, Hilary Schenck.,Russell, John.,Raha, Kaushik.,DeMartino, Michael.,Qin, Donghui.,...&Cheung, Mui.(2018).Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS.ACS MEDICINAL CHEMISTRY LETTERS,9(7).
MLA	Eidam, Hilary Schenck,et al."Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS".ACS MEDICINAL CHEMISTRY LETTERS 9.7(2018).