301219-20-5Relevant academic research and scientific papers
Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains
Shen, Dong-Ming,Shu, Min,Mills, Sander G.,Chapman, Kevin T.,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Siciliano, Salvatore J.,Kwei, Gloria Y.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Schleif, William A.,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael D.,Emini, Emilio A.
, p. 935 - 939 (2007/10/03)
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment
Shu, Min,Loebach, Jennifer L.,Parker, Kerry A.,Mills, Sander G.,Chapman, Kevin T.,Shen, Dong-Ming,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Siciliano, Salvatore J.,Di Salvo, Jerry,Lyons, Kathy,Pivnichny, James V.,Kwei, Gloria Y.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Schleif, William A.,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael D.,Emini, Emilio A.
, p. 947 - 952 (2007/10/03)
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.
