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
Copyright policy )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
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
- Bristol-Myers Squibb (Germany) Germany
Receptors, CCR3, Molecular Conformation, Administration, Oral, Hydrogen Bonding, Rats, Eosinophils, Chemotaxis, Leukocyte, Mice, Structure-Activity Relationship, Dogs, Piperidines, Animals, Cytochrome P-450 Enzyme Inhibitors, Urea
Receptors, CCR3, Molecular Conformation, Administration, Oral, Hydrogen Bonding, Rats, Eosinophils, Chemotaxis, Leukocyte, Mice, Structure-Activity Relationship, Dogs, Piperidines, Animals, Cytochrome P-450 Enzyme Inhibitors, Urea
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