40862-88-2

Upstream product

• 623-47-2 propynoic acid ethyl ester 
• 105728-90-3 2-fluoro-5-methoxybenzaldehyde 
• 623-51-8 ethyl 2-sulfanylacetate 

Downstream Products

• 23046-02-8 5-(methoxy)-1-benzothiophene-2-carboxylic acid 

Relevant academic research and scientific papers

5-methoxybenzothiophene-2-Carboxamides as inhibitors of Clk1/4: Optimization of selectivity and cellular potency

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene-2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5-difluoro benzyl extension to the methylated amide led to the discovery of compound 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 0.43 μM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues.

Development of Selective Clk1 and -4 Inhibitors for Cellular Depletion of Cancer-Relevant Proteins

In cancer cells, kinases of the Clk family control the supply of full-length, functional mRNAs coding for a variety of proteins essential to cell growth and survival. Thus, inhibition of Clks might become a novel anticancer strategy, leading to a selective depletion of cancer-relevant proteins after turnover. On the basis of a Weinreb amide hit compound, we designed and synthesized a diverse set of methoxybenzothiophene-2-carboxamides, of which the N-benzylated derivative showed enhanced Clk1 inhibitory activity. Introduction of a m-fluorine in the benzyl moiety eventually led to the discovery of compound 21b, a potent inhibitor of Clk1 and -4 (IC50 = 7 and 2.3 nM, respectively), exhibiting an unprecedented selectivity over Dyrk1A. 21b triggered the depletion of EGFR, HDAC1, and p70S6 kinase from the cancer cells, with potencies in line with the measured GI50 values. In contrast, the cellular effects of congener 21a, which inhibited Clk1 only weakly, were substantially lower.

BENZOFURAN AND BENZOTHIOPHENE-2-CARBOXYLIC ACID AMIDE DERIVATIVES

The present invention relates to compounds of formula I wherein X, A and R1 to R4 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

VITAMIN D RECEPTOR MODULATORS

The present invention relates to novel, non-secosteroidal, phenyl-benzothiophene compounds with vitamin D receptor (VDR) modulating activity that are less hypercalcemic than 1α,25 dihydroxy vitamin D3. These compounds are useful for treating bone disease

Reaction Pathways for the Cyclization of ortho-Thioalkyl and ortho-Thioaryl Substituted Phenyl Radicals with Alkynes. Reaction of o-Methylthioarenediazonium Tetrafluoroborates with Alkynes to give 2-Substituted Benzothiophenes

An easily effected aromatic annelation is described involving reaction of o-thioalkyl and o-thioaryl substituted phenyl radicals with alkynes to give 2-substituted benzothiophenes; the mechanism is discussed.