Structure–activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists

Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure–activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.

Graphical abstractDesign, synthesis, and structure–activity relationships of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobut-3-ene-1,2-diones are described. Compound 22 demonstrated high potency and excellent selectivity for the CCR1 and desirable pharmacokinetic profiles. Compound 22 was efficacious in the mouse collagen-induced arthritis model.Figure optionsDownload full-size imageDownload as PowerPoint slide