Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Tsou, Hwei‐Ru; MacEwan, Gloria; Birnberg, Gary H.; Grosu, G; Bursavich, Matthew G.; Bard, Joel; Brooijmans, Natasja; Toral‐Barza, Lourdes; Hollander, Irwin; Mansour, Tarek S.; Ayral‐Kaloustian, Semiramis; Yu, Ker

doi:10.1016/j.bmcl.2010.01.135

Cited by 39 publications

(19 citation statements)

References 28 publications

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“…Tsou et al (Weyth) [80] discovered 2-(4-substituted-pyrrolo [2, 3-b] pyridin-3-yl) methylene- 4-hydroxybenzofuran-3(2H)-ones (224-231) as potent and selective mTOR inhibitors. With the indole bearing 4, 6-dihydroxy benzofuranone (223) as the lead, a variety of 4-substituents, including 4-hydroxy phenyl, 4-benzamides and 4-piperidine amides were introduced on the indole.…”

Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

Liu

Wan

et al. 2016

Oncotarget

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Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

Liu

Wan

et al. 2016

Oncotarget

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“…49 This compound was rapidly metabolized by both phase I and phase II metabolism in MLM. However, reducing the ring size of the seven-membered ring with either a morpholine or Nmethylpiperazine ring led to analogues (67 and 68) with greatly improved metabolic stability.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

“…Phase I metabolism studies were conducted with NADPH, while phase I/II studies were conducted with both NADPH and uridine 5′-diphosphoglucuronic acid (UDPGA). 49 Figure 21. In vitro potency and metabolic stability of selected dual EGFR/HER2 inhibitors.…”

Section: ■ Heteroaromatic Compoundsmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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“…thiazole and 1,3,4-thiadiazole have antitumor activity with excellent IG50 and IC50 as depicted in Figure 1 [33][34][35][36][37]. In view of these facts, we report herein the synthesis of a new series of thiazoles and 1,3,4-thiadiazoles bearing indole moiety for the examination of their antitumor activity against the MCF-7 human breast carcinoma cell line.…”

Section: -(1h-indol-3-yl)-3-(p-tolyl)prop-2-en-1-one (3a) [38] and 3mentioning

confidence: 94%

“…In light of these facts, we have synthesized some new thiazole, dihydropyrido [3,2-e] [1,2,4]triazolo [4,3-a]pyrimidine and 1,3,4-thiadiazole derivatives using 3-acetylindole as a common precursor and screened these compounds for their anticancer activities. A literature survey showed that many derivatives of thiazole and 1,3,4-thiadiazole have antitumor thiazole and 1,3,4-thiadiazole have antitumor activity with excellent IG50 and IC50 as depicted in Figure 1 [33][34][35][36][37]. In view of these facts, we report herein the synthesis of a new series of thiazoles and 1,3,4-thiadiazoles bearing indole moiety for the examination of their antitumor activity against the MCF-7 human breast carcinoma cell line.…”

Section: Introductionmentioning

confidence: 94%