Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes.
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
Finke
P E
PE
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. paul_finke@merck.com
Oates
B
B
Mills
S G
SG
MacCoss
M
M
Malkowitz
L
L
Springer
M S
MS
Gould
S L
SL
DeMartino
J A
JA
Carella
A
A
Carver
G
G
Holmes
K
K
Danzeisen
R
R
Hazuda
D
D
Kessler
J
J
Lineberger
J
J
Miller
M
M
Schleif
W A
WA
Emini
E A
EA
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002073:Butanes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D006224:Cricetinae; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009504:Neutrophils / Q000187:drug effects / Q000821:virology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D002073:Butanes; D065100:CCR5 Receptor Antagonists; D010880:Piperidines