1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains.
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Lynch
Christopher L
CL
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. chris_lynch@merck.com
Willoughby
Christopher A
CA
Hale
Jeffrey J
JJ
Holson
Edward J
EJ
Budhu
Richard J
RJ
Gentry
Amy L
AL
Rosauer
Keith G
KG
Caldwell
Charles G
CG
Chen
Ping
P
Mills
Sander G
SG
MacCoss
Malcolm
M
Berk
Scott
S
Chen
Liya
L
Chapman
Kevin T
KT
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; D004285:Dogs; D006207:Half-Life; D006801:Humans; D007963:Leukocytes, Mononuclear; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; C032727:piperidine