Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase Α₂α

Abstract

The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha 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 sub-micromolar inhibitor of cPLA2alpha 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.

Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model

“…A previous study on cPLA2 alpha-deficient mice [10] led to the development of certain compounds and their examination in pharmacological studies [31][32][33][34]. However, it remained unclear whether the phenotype of cPLA2 alpha-deficient mice should be attributed to the reduction in eicosanoid production such as LTB 4 or PGE 2 [10].…”

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…During the course of the SAR study which eventually led to the compound Ecopladib, a C-N coupling with JohnPhos was employed (Scheme 41). [198] It is notable that the presence of multiple acidic hydrogens in the aryl halide substrate did not interfere with the coupling which had previously been successfully applied in the transformation of simpler members of the series. [199] Augustyns at the University of Antwerp utilized the coupling of a primary amine and bromobenzene during the course of work on the synthesis of selective dipeptidyl peptidase II inhibitors which have potential for the treatment of a range of diseases (Scheme 42).…”

Biarylphosphanliganden in der palladiumkatalysierten Aminierung

“…Im Verlauf der Struktur-Aktivitäts-Studie, die schließlich zu Ecopladib führte, wurde eine C-N-Kupplung mit JohnPhos eingesetzt (Schema 41). [198] Es ist bemerkenswert, dass mehrere acide Protonen am ArylhalogenidSubstrat die Kupplung nicht beeinträchtigten. [199] Augustyns [201] Wegen der kurzen Halbwertszeit von 18 F (t 1/2 = 109.6 min) müssen die Reaktionen schnell ablaufen.…”