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

• Published in: Bioorganic & medicinal chemistry letters 2008-01, Vol.18 (2), p.576-585
• Main Authors: Santella, Joseph B., Gardner, Daniel S., Yao, Wenqing, Shi, Chongsheng, Reddy, Prabhakar, Tebben, Andrew J., DeLucca, George V., Wacker, Dean A., Watson, Paul S., Welch, Patricia K., Wadman, Eric A., Davies, Paul, Solomon, Kimberly A., Graden, Dani M., Yeleswaram, Swamy, Mandlekar, Sandhya, Kariv, Ilona, Decicco, Carl P., Ko, Soo S., Carter, Percy H., Duncia, John V.
• Format: Article
• Language: English
• Subjects: Ab initio; Acyclic scaffold; Administration, Oral; Animals; Asthma; Biological and medical sciences; BMS-639623; CCR3 antagonist; Chemotaxis, Leukocyte - drug effects; Conformational analysis; Cytochrome P-450 Enzyme Inhibitors; Development candidate; Dogs; Eosinophil chemotaxis; Eosinophils - cytology; Eosinophils - drug effects; Hydrogen Bonding; Medical sciences; Mice; Molecular Conformation; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Rats; Receptors, CCR3 - antagonists & inhibitors; Respiratory system; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacokinetics; Urea - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.11.067

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. It was found that the α-methyl group lowered protein binding and the β-hydroxyl group lowered affinity for CYP2D6. Urea 31 (BMS-639623) with a chemotaxis IC 50 = 38 pM for eosinophils was chosen to enter clinical development. 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.