Tomas Eriksson

Spirocyclic compounds, potent CCR1 antagonists

Conformationally constrained spirocycles (17-23) and (31-36) were synthesised. In vitro data revealed that these compounds are CCR1 antagonists with sub-nanomolar potency. In a functional assay 22, 23 and 36 inhibited CCR1 mediated chemotaxis with an IC50 value of 2, 2.6 and 68nM, respectively.

Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists.

A series of fused bicyclic and urea derivatives of spirocyclic compounds were designed, synthesised and evaluated in vitro as potent CCR1 antagonists. In particular, 4 (7nM), 44 (1.3nM), 48 (0.89nM) and 50 (0.63nM) were the most potent hCCR1 antagonists in this series of compounds. Moreover, some of these substances demonstrated good rodent cross-over, especially 46 which exhibited very high rat CCR1 binding affinity with an IC50 value of 16nM.