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3-嘧啶-4-基-恶唑烷-2-酮类化合物作为口服生物可利用且可穿透血脑屏障的突变型异柠檬酸脱氢酶1抑制剂的优化

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors.

作者信息

Zhao Qian, Manning James R, Sutton James, Costales Abran, Sendzik Martin, Shafer Cynthia M, Levell Julian R, Liu Gang, Caferro Thomas, Cho Young Shin, Palermo Mark, Chenail Gregg, Dooley Julia, Villalba Brian, Farsidjani Ali, Chen Jinyun, Dodd Stephanie, Gould Ty, Liang Guiqing, Slocum Kelly, Pu Minying, Firestone Brant, Growney Joseph, Heimbach Tycho, Pagliarini Raymond

机构信息

Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.

Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

出版信息

ACS Med Chem Lett. 2018 Jun 11;9(7):746-751. doi: 10.1021/acsmedchemlett.8b00182. eCollection 2018 Jul 12.

DOI:10.1021/acsmedchemlett.8b00182
PMID:30034612
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6047033/
Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1. This Letter describes SAR exploration focused on improving both the and metabolic stability of the compounds, leading to the identification of as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, efficiently inhibited the production of the biomarker 2-HG.

摘要

突变型异柠檬酸脱氢酶1（IDH1）是治疗急性髓系白血病（AML）、神经胶质瘤和胶质母细胞瘤等多种癌症的一个有吸引力的治疗靶点。我们已评估了3-嘧啶-4-基-恶唑烷-2-酮作为与IDH1的变构诱导口袋结合的突变型IDH1抑制剂。本信函描述了旨在提高化合物的[此处原文缺失部分内容]和代谢稳定性的构效关系探索，从而鉴定出[此处原文缺失部分内容]作为一种强效且选择性的突变型IDH1抑制剂，该抑制剂在啮齿动物中已证明具有脑渗透性和出色的口服生物利用度。在一项临床前患者来源的IDH1突变异种移植肿瘤模型研究中，[此处原文缺失部分内容]有效抑制了生物标志物2-羟基戊二酸（2-HG）的产生。

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ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121. doi: 10.1021/acsmedchemlett.7b00342. eCollection 2017 Oct 12.
2
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3
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