143128-45-4

Upstream product

• 67-36-7 4-phenoxy benzaldehyde 
• 540-38-5 p-Iodophenol 
• 459-57-4 4-fluorobenzaldehyde 
• 1194-02-1 4-fluorobenzonitrile 
• 143128-36-3 4-(3-dimethylaminoprop-1-enyl)-4'-iododiphenyl ether 
• 101-84-8 diphenylether 

Downstream Products

• 158771-58-5 4-([1,1'-biphenyl]-4-yloxy)benzaldehyde 
• 21120-69-4 4-(4-iodo-phenoxy)-benzoic acid 

Relevant academic research and scientific papers

Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors

The sphingosine 1-phosphate (S1P) signaling pathway is an attractive target for pharmacological manipulation due to its involvement in cancer progression and immune cell chemotaxis. The synthesis of S1P is catalyzed by the action of sphingosine kinase 1 or 2 (SphK1 or SphK2) on sphingosine and ATP. While potent and selective inhibitors of SphK1 or SphK2 have been reported, development of potent dual SphK1/SphK2 inhibitors are still needed. Towards this end, we report the structure–activity relationship profiling of 2-(hydroxymethyl)pyrrolidine-based inhibitors with 22d being the most potent dual SphK1/SphK2 inhibitor (SphK1 Ki = 0.679 μM, SphK2 Ki = 0.951 μM) reported in this series. 22d inhibited the growth of engineered Saccharomyces cerevisiae and decreased S1P levels in histiocytic lymphoma myeloid cell line (U937 cells), demonstrating inhibition of SphK1 and 2 in vitro. Molecular modeling studies of 22d docked inside the Sph binding pocket of both SphK1 and SphK2 indicate essential hydrogen bond between the 2-(hydroxymethyl)pyrrolidine head to interact with aspartic acid and serine residues near the ATP binding pocket, which provide the basis for dual inhibition. In addition, the dodecyl tail adopts a “J-shape” conformation found in crystal structure of sphingosine bound to SphK1. Collectively, these studies provide insight into the intermolecular interactions in the SphK1 and 2 active sites to achieve maximal dual inhibitory activity.

(Aryloxy)aryl semicarbazones and related compounds: A novel class of anticonvulsant agents possessing high activity in the maximal electroshock screen

A number of (aryloxy)aryl semicarbazones and related compounds were synthesized and evaluated far anticonvulsant activities. After intraperitoneal injection to mice, the semicarbazones were examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and neurotoxicity (NT) screens. The results indicated that greater protection was obtained in the MES test than the scPTZ screen. Quantitation of approximately one-third of the compounds revealed an average protection index (PI, i.e. TD50/ED50) of approximately 9. After oral administration to rats, a number of compounds displayed significant potencies in the MES screen (ED50 of 1-5 mg/kg) accompanied by very high protection indices. In fact over half the compounds had PI figures of greater than 100, and two were in excess of 300. The compounds were essentially inactive in the scPTZ and NT screens after oral administration to rats. Various compounds displayed greater potencies and PI figures in the mouse intraperitoneal and rat oral screens than three reference clinically used drugs. The data generated supported a binding site hypothesis. Quantitative structure-activity relationships indicated a number of physicochemical parameters which contributed to activity in the MES screen. X-ray crystallography of five compounds suggested the importance of certain interatomic distances and bond angles for activity in the mouse and rat MES screens.

ARYL DERIVATIVES

The invention concerns an aryl derivative of the formula I, wherein Ar1 is optionally substituted phenyl, naphthyl or a heterocyclic moiety, and X1 is oxy, thio, sulphinyl, sulphonyl, difluoromethylene, imino, (1-4C)alkylimino or optionally substituted (1-4C) alkylene, or X1 is a group of the formula wherein X4 is oxy, thio, sulphinyl, sulphonyl or carbonyl and each R is hydrogen, methyl or ethyl each of Ar2 and Ar3 is optionally substituted phenylene X2 is oxy, thio, sulphinyl or sulphonyl R1 is (1-4C)alkyl and R2 and R3 together form a group of the formula A1 X3 A2 which together with the carbon atom to which A1 and A2 are attached define a ring having 5 to 7 ring atoms, wherein each of A1 and A2 is (1-3C) alkylene and X3 is oxy, thio, sulphinyl or sulphonyl which compounds are inhibitors of 5-lipoxygenase and are useful in the treatment of inflammatory or allergic disease