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PMID: 11606733 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 22 ·2001-10-23 ·Pages 12718-23

Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J, Hou Y, Endres M, Palani A, Shapiro S, Clader JW, Greenlee WJ, Tagat JR, McCombie S, Cox K, Fawzi AB, Chou CC, Pugliese-Sivo C, Davies L, Moreno ME, Ho DD, Trkola A, Stoddart CA, Moore JP, Reyes GR, Baroudy BM

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.

MeSH Terms

Acquired Immunodeficiency Syndrome/drug therapy Animals Anti-HIV Agents/pharmacology CCR5 Receptor Antagonists Chemokine CCL5/antagonists & inhibitors Cyclic N-Oxides/pharmacokinetics,pharmacology,therapeutic use HIV-1/drug effects Humans Macaca fascicularis Male Mice Mice, SCID Oximes Piperidines Pyridines/pharmacokinetics,pharmacology,therapeutic use Rats Rats, Sprague-Dawley

Chemicals

Anti-HIV Agents CCR5 Receptor Antagonists Chemokine CCL5 Cyclic N-Oxides Oximes Piperidines Pyridines Ancriviroc

Authors & Affiliations

25 authors, click to expand affiliations / ORCID

Strizki J M

Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.

Xu S

Wagner N E

Wojcik L

Liu J

Hou Y

Endres M

Palani A

Shapiro S

Clader J W

Greenlee W J

Tagat J R

McCombie S

Cox K

Fawzi A B

Chou C C

Pugliese-Sivo C

Davies L

Moreno M E

Ho D D

Trkola A

Stoddart C A

Moore J P

Reyes G R

Baroudy B M

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.221375398

Published

2001-10-23

Epub

2001-00-16

Pages

12718-23

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC60120

Subset

Grants

NIAID NIH HHS · R01 AI041420 · United States

NIAID NIH HHS · R01 AI41420 · United States

External Links

PubMed source DOI: 10.1073/pnas.221375398 PMC Full Text View journal details

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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.

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