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Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.发现 4-{4-[(3R)-3-甲基吗啉-4-基]-6-[1-(甲磺酰基)环丙基]嘧啶-2-基}-1H-吲哚（AZ20）：一种有效的和选择性的 ATR 蛋白激酶抑制剂，具有体内单药抗肿瘤活性。
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The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5.醛氧化酶和黄嘌呤氧化酶在代谢型谷氨酸受体亚型 5 的新型负变构调节剂生物转化中的作用。
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Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents.发现强效和选择性的共济失调毛细血管扩张突变和 Rad3 相关（ATR）蛋白激酶抑制剂作为潜在的抗癌药物。
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新型、强效且选择性的氮杂苯并咪唑类化合物（ABI）作为ATR抑制剂的基于结构的药物设计

Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors.

作者信息

Barsanti Paul A, Pan Yue, Lu Yipin, Jain Rama, Cox Matthew, Aversa Robert J, Dillon Michael P, Elling Robert, Hu Cheng, Jin Xianming, Knapp Mark, Lan Jiong, Ramurthy Savithri, Rudewicz Patrick, Setti Lina, Subramanian Sharadha, Mathur Michelle, Taricani Lorena, Thomas George, Xiao Linda, Yue Qin

机构信息

Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.

出版信息

ACS Med Chem Lett. 2014 Oct 30;6(1):42-6. doi: 10.1021/ml500352s. eCollection 2015 Jan 8.

DOI:10.1021/ml500352s
PMID:25589928
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4291699/
Abstract

Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered.

摘要

化合物13是通过对ATR生化高通量筛选命中化合物1进行结构优化发现的。ABI系列对ATR具有强效和选择性。引入6-氮杂吲哚使细胞活性显著提高，但与不良的药代动力学和hERG离子通道抑制有关。药物代谢动力学实验表明，CYP P450和AO代谢以及Pgp和BCRP外排是观察到的药代动力学的主要原因机制。该系列还存在由吗啉和吲哚部分共同存在驱动的CYP3A4时间依赖性抑制风险。在6-氮杂吲哚中引入相邻的氟或氮解决了遇到的许多不同的药物化学问题。