title: 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.
abstract: 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.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Strizki
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: N E
authors.initials: NE
authors.lastname: Wagner
authors.forename: L
authors.initials: L
authors.lastname: Wojcik
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
authors.forename: M
authors.initials: M
authors.lastname: Endres
authors.forename: A
authors.initials: A
authors.lastname: Palani
authors.forename: S
authors.initials: S
authors.lastname: Shapiro
authors.forename: J W
authors.initials: JW
authors.lastname: Clader
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: J R
authors.initials: JR
authors.lastname: Tagat
authors.forename: S
authors.initials: S
authors.lastname: McCombie
authors.forename: K
authors.initials: K
authors.lastname: Cox
authors.forename: A B
authors.initials: AB
authors.lastname: Fawzi
authors.forename: C C
authors.initials: CC
authors.lastname: Chou
authors.forename: C
authors.initials: C
authors.lastname: Pugliese-Sivo
authors.forename: L
authors.initials: L
authors.lastname: Davies
authors.forename: M E
authors.initials: ME
authors.lastname: Moreno
authors.forename: D D
authors.initials: DD
authors.lastname: Ho
authors.forename: A
authors.initials: A
authors.lastname: Trkola
authors.forename: C A
authors.initials: CA
authors.lastname: Stoddart
authors.forename: J P
authors.initials: JP
authors.lastname: Moore
authors.forename: G R
authors.initials: GR
authors.lastname: Reyes
authors.forename: B M
authors.initials: BM
authors.lastname: Baroudy
mesh_terms: 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
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; C438583:Ancriviroc