872674-45-8

Upstream product

• 61220-51-7 2-(5-chloro-1H-indol-3-yl)ethanol 
• 163160-55-2 (5-chloro-1H-indol-3-yl)oxoacetic acid methylester 
• 17422-32-1 5-chloro-1H-indole 
• 1026795-49-2 methanesulfonic acid 2-(5-chloro-1H-indol-3-yl)-ethyl ester 
• 99-76-3 methyl 4-hydroxylbenzoate 

Downstream Products

• 1026938-90-8 C₁₈H₁₅BrClNO₃ 
• 934284-92-1 4-{2-[2-bromo-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid 
• 934284-90-9 methyl 4-{2-[2-bromo-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoate 
• 872674-46-9 methyl 4-[2-[5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy]benzoate 

Relevant academic research and scientific papers

Discovery of ecopladib, an indole inhibitor of cytosolic phospholipase A2α

The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2α (cPLA 2α, type IVA phospholipase) are described. Inhibitors of cPLA2α are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a submicromolar inhibitor of cPLA2α in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.

Inhibition of cytosolic phospholipase A2α: Hit to lead optimization

Compound 1 was previously reported to be a potent inhibitor of cPLA 2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzole acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ- linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.