SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo.
We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.
Strizki
J M
JM
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Xu
S
S
Wagner
N E
NE
Wojcik
L
L
Liu
J
J
Hou
Y
Y
Endres
M
M
Palani
A
A
Shapiro
S
S
Clader
J W
JW
Greenlee
W J
WJ
Tagat
J R
JR
McCombie
S
S
Cox
K
K
Fawzi
A B
AB
Chou
C C
CC
Pugliese-Sivo
C
C
Davies
L
L
Moreno
M E
ME
Ho
D D
DD
Trkola
A
A
Stoddart
C A
CA
Moore
J P
JP
Reyes
G R
GR
Baroudy
B M
BM
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010091:Oximes; D010880:Piperidines; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; C438583:Ancriviroc