| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1365372 | Bioorganic & Medicinal Chemistry Letters | 2008 | 10 Pages |
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 IC50 = 38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Graphical abstractConformational 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 IC50 = 38 pM for eosinophils was chosen to enter clinical development.Figure optionsDownload full-size imageDownload as PowerPoint slide
