Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure-activity relationships for substituted 2-Aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes.
(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).
Finke
P E
PE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. paul_finke@merck.com
Meurer
L C
LC
Oates
B
B
Mills
S G
SG
MacCoss
M
M
Malkowitz
L
L
Springer
M S
MS
Daugherty
B L
BL
Gould
S L
SL
DeMartino
J A
JA
Siciliano
S J
SJ
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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002073:Butanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002082:Butylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054407:Chemokine CCL4; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D019380:Anti-HIV Agents; D002073:Butanes; D002082:Butylamines; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010880:Piperidines; D019713:Receptors, CCR5; D013449:Sulfonamides