CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines.
A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.
Lynch
Christopher L
CL
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. chris_lynch@merck.com
Gentry
Amy L
AL
Hale
Jeffrey J
JJ
Mills
Sander G
SG
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
Doss
George
G
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
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065100:CCR5 Receptor Antagonists; D007555:Isoxazoles; D011759:Pyrrolidines