Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor.
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
Shankaran
K
K
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. kothandaraman_shankaran@merck.com
Donnelly
Karla L
KL
Shah
Shrenik K
SK
Guthikonda
Ravindra N
RN
MacCoss
Malcolm
M
Mills
Sander G
SG
Gould
Sandra L
SL
Malkowitz
Lorraine
L
Siciliano
Salvatore J
SJ
Springer
Martin S
MS
Carella
Anthony
A
Carver
Gwen
G
Hazuda
Daria
D
Holmes
Karen
K
Kessler
Joseph
J
Lineberger
Janet
J
Miller
Michael D
MD
Emini
Emilio A
EA
Schleif
William A
WA
D000085:Acetates / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D002455:Cell Division / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000085:Acetates; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines