From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis.

Abstract Conformational analysis of trans -1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn -α-methyl-β-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the α-methyl group to the urea lowered protein binding and that the β-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the α-methyl group governs the spatial orientation of three key functionalities within the molecule. α-Methyl-β-hydroxypropyl urea 31 with a chemotaxis IC 50  = 38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.