1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains.
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Willoughby
Christopher A
CA
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. cwilloug@amgen.com
Rosauer
Keith G
KG
Hale
Jeffery J
JJ
Budhu
Richard J
RJ
Mills
Sander G
SG
Chapman
Kevin T
KT
MacCoss
Malcolm
M
Malkowitz
Lorraine
L
Springer
Martin S
MS
Gould
Sandra L
SL
DeMartino
Julie A
JA
Siciliano
Salvatore J
SJ
Cascieri
Margaret A
MA
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
M
Emini
Emilio A
EA
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054407:Chemokine CCL4; D006224:Cricetinae; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010880:Piperidines; D011759:Pyrrolidines