Small molecule inhibitors of the CCR2b receptor. Part 1: Discovery and optimization of homopiperazine derivatives.

N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.

Small molecule antagonists of the CCR2b receptor. Part 2: Discovery process and initial structure-activity relationships of diamine derivatives.

Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays.