Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
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
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发表时间：
2018-07-01
影响因子：
4.2
通讯作者：
Cheung, Mui
中科院分区：
文献类型：
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作者：
Eidam, Hilary Schenck;Russell, John;Cheung, Mui
腹痛和排便习惯异常是肠易激综合征 (IBS) 患者未得到充分治疗的主要症状。尽管 IBS 的病因尚不完全清楚，但胃肠道 (GI) 的许多功能均受肠神经系统 (ENS) 调节。炎症或应激诱导的生长因子或细胞因子的表达可能导致胃肠道内脏传入神经元的过度神经支配，并导致 IBS 的病理生理学。转染期间重排 (RET) 是一种神经元生长因子受体酪氨酸激酶，对于 ENS 的发育至关重要，例如先天性巨结肠患者携带 RET 功能丧失突变，缺乏正常的结肠神经支配，导致结肠梗阻。同样，成人 ENS 中的 RET 信号通过促进突触形成、信号传递和神经元可塑性来维持神经元功能。抑制 ENS 中的 RET 代表了一种使神经元功能和 IBS 患者症状正常化的新治疗策略。在此，我们描述了我们在优化该系列的效力、选择性和致突变性方面的筛选工作和随后的构效关系（SAR），从而发现了一流的肠道限制性 RET 激酶抑制剂， 2-(4-(4-乙氧基-6-氧代-1,6-二氢吡啶-3-基)-2-氟苯基)-N-(5-(1,1,1-三氟-2-甲基丙-2-基)异恶唑-3-基)乙酰胺（IS，GSK3179106），作为治疗IBS的临床候选药物。 GSK3179106 是一种有效的、选择性的、肠道限制性的吡啶酮铰链结合物小分子 RET 激酶抑制剂，RET IC50 为 0.3 nM，在体内有效。
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.