Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment.
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.
Shu
Min
M
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. min_shu@merck.com
Loebach
Jennifer L
JL
Parker
Kerry A
KA
Mills
Sander G
SG
Chapman
Kevin T
KT
Shen
Dong-Ming
DM
Malkowitz
Lorraine
L
Springer
Martin S
MS
Gould
Sandra L
SL
DeMartino
Julie A
JA
Siciliano
Salvatore J
SJ
Salvo
Jerry Di
JD
Lyons
Kathy
K
Pivnichny
James V
JV
Kwei
Gloria Y
GY
Carella
Anthony
A
Carver
Gwen
G
Holmes
Karen
K
Schleif
William A
WA
Danzeisen
Renee
R
Hazuda
Daria
D
Kessler
Joseph
J
Lineberger
Janet
J
Miller
Michael D
MD
Emini
Emilio A
EA
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles