Bioorganic and Medicinal Chemistry Letters p. 576 - 585 (2008)
Update date:2022-09-26
Topics:
Santella III, 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.
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.
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