کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1365372 | 981560 | 2008 | 10 صفحه PDF | دانلود رایگان |
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.
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 IC50 = 38 pM for eosinophils was chosen to enter clinical development.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 18, Issue 2, 15 January 2008, Pages 576–585