299181-56-9

Upstream product

• 110-91-8 morpholine 
• 2267-40-5 3-chlorosulfonyl-4-fluoro-benzoic acid 
• 456-22-4 4-Fluorobenzoic acid 
• 299181-55-8 methyl 4-fluoro-3-(morpholinosulfonyl)benzoate 

Downstream Products

• 299181-62-7 3-(morpholine-4-sulfonyl)-4-morpholin-4-yl-benzoic acid 
• 1423715-23-4 methyl 4-hydrazinyl-3-(morpholinosulfonyl)benzoate 
• 299181-55-8 methyl 4-fluoro-3-(morpholinosulfonyl)benzoate 
• 299181-69-4 4-hydroxy-3-(morpholine-4-sulfonyl)-benzoic acid 

Relevant academic research and scientific papers

Design, Synthesis,In VitroandIn VivoCharacterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in down Syndrome

Intracellular chloride concentration [Cl-]iis defective in several neurological disorders. In neurons, [Cl-]iis mainly regulated by the action of the Na+-K+-Cl-importer NKCC1 and the K+-Cl-exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead within vivoefficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.

MODULATORS OF INTRACELLULAR CHLORIDE CONCENTRATION

The present invention relates to a compound of Formula la, lb and Ic, (Formula Ia) a pharmaceutical composition comprising the same and their use in the treatment or prevention of pathological conditions associated to depolarizing GABAergic transmission including, for example, Down syndrome and autism.

Synthesis and Biological Evaluation of 4-Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII

With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (series 5 a–r and series 7 a–q) and evaluated their inhibition profiles against five isoforms of the zinc-containing human carbonic anhydrase (hCA, EC 4.2.1.1): cytosolic hCA I and II, and the transmembrane isozymes hCA IV, IX, and XII. Compounds 5 a–r were found to selectively inhibit hCA II in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) acts as a “prodrug” inhibitor and is hydrolyzed by the esterase activity of hCA to form 2-hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7 a–q) were found to be very weak or ineffective as inhibitors of the housekeeping off-target hCA isoforms I and II, and effectively inhibited the transmembrane tumor-associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.

Synthesis of (bis)sulfonic acid, (bis)benzamides as follicle-stimulating hormone (FSH) antagonists.

Screening efforts identified (bis)sulfonic acid, (bis)benzamides (1-3) as compounds that interact with the follicle stimulating-hormone receptor (FSHR) and inhibit FSH-stimulated cAMP accumulation with IC(50) values in the low micromolar range. Structure-activity relationship studies using novel analogues of 1-3 revealed that two phenylsulfonic acid moieties were necessary for activity and that the carbon-carbon double bond of the stilbene sub-series was the optimum spacer connecting these groups. Selected analogues (2, 14, and 50) were also able to block FSHR-dependent estradiol production in rat primary ovarian granulosa cells and progesterone secretion in a clonal mouse adrenal Y1 cell line. IC(50) values for these compounds in these assays were in the low micromolar range. Optimization of the benzoic acid side chains of 1-3 led to gains in selectivity versus activity at the thyroid stimulating hormone (TSH) receptor (TSHR). For instance, while stilbene (bis)sulfonic acid congener 2 was only 10-fold selective for FSHR over TSHR, analogue 50 with an IC(50) value of 0.9 microM in the FSHR-cAMP assay was essentially inactive at 30 microM in the TSHR-cAMP assay.

Aryl sulfonic acids and derivatives as FSH antagonists

This invention provides compounds of formula I having the structure wherein R1, Ar, Ar′, and Q are as defined in the specification, or a pharmaceutically acceptable salt thereof, which are useful as contraceptive agents.