Author/Authors :
Min Shu، نويسنده , , Jennifer L. Loebach، نويسنده , , Kerry A Parker، نويسنده , , Sander G. Mills، نويسنده , , Kevin T. Chapman، نويسنده , , Dong-Ming Shen، نويسنده , , Lorraine Malkowitz، نويسنده , , Martin S. Springer، نويسنده , , Sandra L. Gould، نويسنده , , Julie A. DeMartino، نويسنده , , Salvatore J. Siciliano، نويسنده , , Jerry Di Salvo، نويسنده , , Kathy Lyons، نويسنده , , James V. Pivnichny، نويسنده , , Gloria Y. Kwei، نويسنده , , Anthony Carella، نويسنده , , Gwen Carver، نويسنده , , Karen Holmes، نويسنده , , William A. Schleif، نويسنده , , Renee Danzeisen، نويسنده , , et al.، نويسنده ,
Abstract :
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
Keywords :
e-mail: min_shu@merck.com , dongming_shen@merck.com , Pyrazole.* Corresponding authors. Fax: +1-732-594-8080 , HIV-1 , CCR5 antagonist , antiviral
