1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV.
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Lynch
Christopher L
CL
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. chris_lynch@merck.com
Hale
Jeffrey J
JJ
Budhu
Richard J
RJ
Gentry
Amy L
AL
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* / Q000493:pharmacokinetics / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D054407:Chemokine CCL4; D006224:Cricetinae; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007202:Indicators and Reagents; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D007202:Indicators and Reagents; D019402:Macrophage Inflammatory Proteins; D011759:Pyrrolidines