83783-28-2

Upstream product

• 15861-24-2 1H-indole-5-carbonitrile 
• 74-96-4 ethyl bromide 
• 75-03-6 ethyl iodide 

Downstream Products

• 1613252-38-2 (E)-1-ethyl-3-(2-((methoxyimino)methyl)phenyl)-1H-indole-5-carbonitrile 

Relevant academic research and scientific papers

Structure-based linker exploration: Discovery of 1-ethyl-1H-indole analogs as novel ATX inhibitors

Aiming to develop novel ATX inhibitors, an indole-3-carboxylic acid lead Indole-1 was identified through high-throughput screening (HTS) efforts. The Indole-1 analogs 1–7 was firstly prepared which exerted mild activity comparable to Indole-1 (740 nM) in ATX enzyme assay. Further structural modification to identify type IV ATX inhibitors was proceeded through derivatization of the indole-3-carboxylic acid group. Resultantly, compounds 8–17 containing acyl hydrazone linker displayed poor activity (over 3.49 μM). Alternatively, replacing the acylhydrazone linker with urea counterpart by the amide bond reversal principle, the acquired compounds 18–22 achieved obvious improvements with submicromolar activities. Furthermore, with the aim to reducing cLogP, the thiazole ring of 18–22 was altered to the benzamide (23–32) with the urea linker unchanged. Remarkably, the benzamide derivative 24 with 4-hydroxy piperidine fragment was identified which exhibited prominent activity with IC50 value of 2.3 nM. Especially, dedicated molecular docking study was throughout the modification process which qualified 24 as optimal entity in accordance with the ATX inhibitory results.

ATX inhibitor based on indole parent nucleus, and preparation method and application thereof

The invention belongs to the technical field of medicines, and relates to an ATX inhibitor based on an indole parent nucleus and an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method of the ATX inhibitor and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug, and a pharmaceutical composition containing the compound. The indole derivative and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug of the indole derivative is shown as a general formula I which is described in thespecification. In the general formula I, L, X and R1 to R8 are as described in the claims and the specification. The indole derivative provided by the invention has relatively strong ATX inhibitory activity in vitro, so the indole derivative can be used for preparing medicines for treating and/or preventing cancers and fibrotic diseases.

Discovery of Novel Indole-Based Allosteric Highly Potent ATX Inhibitors with Great in Vivo Efficacy in a Mouse Lung Fibrosis Model

Autotaxin (ATX) is the dominant catalytic enzyme accounting for the lipid mediator lysophosphatidic acid (LPA) through hydrolysis of lysophosphatidylcholine (LPC). There is great interest in developing nonacidic ATX inhibitors with a specific binding mode to serve as potential in vivo effective therapeutic tools. Herein, dating from a high-throughput screening (HTS) product Indole-1 (740 nM), a dedicated optimization campaign was implemented through derivatizing the-COOH group to versatile linkers that well-bridged the indole skeleton and the hydrophobic pocket binding groups. Ultimately, it was established that the coexistence of a carbamate linker and-OH-group-containing amines could generally furnish excellent indole-based ATX inhibitors with even below 1 nM in vitro activities. Two optimal entities were advanced to a bleomycin-induced mice pulmonary fibrosis model, which exerted promising efficacy in alleviating the damaged lung texture caused by bleomycin exposure. The novel carbamate-containing indole-based ATX inhibitors with a concrete binding mode may contribute to the identification of potential therapeutic agents to intervene in fibrotic diseases.

Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects

ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indole-based lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity.

Introducing tetramethylurea as a new methylene precursor: a microwave-assisted RuCl3-catalyzed cross dehydrogenative coupling approach to bis(indolyl)methanes

Herein we report a microwave assisted Ru(iii)/TBHP-mediated reaction of indoles with tetramethylurea (TMU) synthesizing symmetrical as well as unsymmetrical bis(indolyl)methanes, where TMU acts as a methylenating agent. This is the first report where TMU is used as a methylene source. Moreover, the synthesis of unsymmetrical bis(indolyl)methanes by using a carbon precursor is also reported herein for the first time. Various substituted indoles are used for the reaction. The reaction is high yielding and takes a much shorter time to accomplish compared to the existing methods.

Palladium catalyzed dual C-H functionalization of indoles with cyclic diaryliodoniums, an approach to ring fused carbazole derivatives

Palladium(ii)-catalyzed dual C-H functionalization of indoles with cyclic diaryliodoniums was successfully achieved, providing a concise method to synthesize dibenzocarbazoles. In a single operation, two C-C bonds and one ring were formed. The reaction was ligand free and tolerated air and moisture conditions.

Cu(ii)-catalyzed C-H (SP3) oxidation and C-N cleavage: Base-switched methylenation and formylation using tetramethylethylenediamine as a carbon source

Base-switched methylenation and formylation using tetramethylethylenediamine (TMEDA) as a carbon source have been achieved under mild conditions, catalyzed by CuCl2, with atmospheric oxygen as oxidant. Bisindolylmethanes, diphenylmethanes and 3-formylindoles were synthesized with excellent regioselectivity and good yield.

Aromatic Amidines: Comparison of Their Ability to Block Respiratory Syncytial Virus Induced Cell Fusion and to Inhibit Plasmin, Urokinase, Thrombin, and Trypsin

Two series of amidine derivatives consisting of a total of 24 compounds were examined for a correlation between their blocking effect on respiratory syncytial virus induced cell fusion and their inhibitory activity against selected trypsin-like protease.A