Author/Authors :
Joseph B. Santella III، نويسنده , , Daniel S. Gardner، نويسنده , , Wenqing Yao، نويسنده , , Chongsheng Shi، نويسنده , , Prabhakar Reddy، نويسنده , , Andrew J. Tebben، نويسنده , , George V. DeLucca، نويسنده , , Dean A. Wacker، نويسنده , , Paul S. Watson، نويسنده , , Patricia K. Welch، نويسنده , , Eric A. Wadman، نويسنده , , Paul Davies، نويسنده , , Kimberly A. Solomon، نويسنده , , Dani M. Graden، نويسنده , , Swamy Yeleswaram، نويسنده , , Sandhya Mandlekar، نويسنده , , Ilona Kariv، نويسنده , , Carl P. Decicco، نويسنده , , Soo S. Ko، نويسنده , , Percy H. Carter، نويسنده , , et al.، نويسنده ,
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 IC50 = 38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Keywords :
BMS-639623 , CCR3 antagonist , Development candidate , asthma , Conformational analysis , Acyclic scaffold , Eosinophil chemotaxis , Ab initio
