Kathleen Cox

Merck & Co., Inc., Rahway, NJ, USA (United States)

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William J. Greenlee

Merck & Co., Inc., Rahway, NJ, USA (United States)

John W. Clader

Merck & Co., Inc., Rahway, NJ, USA (United States)

R. Graham Cooks

Purdue University West Lafayette

Diane E. Grotz

Merck & Co., Inc., Rahway, NJ, USA (United States)

Julie Strizki

Merck & Co., Inc., Rahway, NJ, USA (United States)

Bahige M. Baroudy

Duke University

Andrew W. Stamford

Tri-Institutional Therapeutics Discovery Institute

Eric M. Parker

Universidad Tecnológica de Panamá

Matthew Kennedy

Merck & Co., Inc., Rahway, NJ, USA (United States)

Jared N. Cumming

Acorn

Cooperative Institutions

Merck & Co., Inc., Rahway, NJ, USA (United States)

195

United States Military Academy

Merck (France)

Cornell University

Harvard University

Aaron Diamond AIDS Research Center

Rockefeller University

Chinese Academy of Medical Sciences & Peking Union Medical College

King's College Hospital

Rutgers, The State University of New Jersey

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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 infectionin vitroandin vivo

Proceedings of the National Academy of Sciences (2001)

Julie Strizki Serena Xu Nicole Wagner Lisa Wojcik Jia Liu

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.

CCR5 receptor antagonist

IC50

Entry inhibitor

10.1073/pnas.221375398

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Citations (307)

Improving the Oral Efficacy of CNS Drug Candidates: Discovery of Highly Orally Efficacious Piperidinyl Piperidine M₂ Muscarinic Receptor Antagonists

Journal of Medicinal Chemistry (2002)

Yuguang Wang Samuel Chackalamannil Zhiyong Hu William J. Greenlee John W. Clader

In search of a backup M2 muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.

Lipophilicity

Piperidine

Muscarinic antagonist

10.1021/jm0255163

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Citations (10)

CCDC 1451339: Experimental Crystal Structure Determination

Jack D. Scott Sarah W. Li Andrew P. J. Brunskill Xia Chen Kathleen Cox

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Efficient trapping and collision‐induced dissociation of high‐mass cluster ions using mixed target gases in the quadrupole ion trap

Rapid Communications in Mass Spectrometry (1992)

Kenneth L. Morand Kathleen Cox R. Graham Cooks

Abstract Heavy target gases (neon, argon, krypton or xenon), when added in small amounts to the helium buffer gas in the quadruple ion trap, improve both the trapping efficiency of cesium iodide cluster ions of high mass‐to‐charge ratio and the internal energy deposition during collision‐induced dussociation experiments.

Krypton

Quadrupole ion trap

Collision-induced dissociation

Buffer gas

10.1002/rcm.1290060807

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Citations (29)

Humanistic Approach to the Typical Medical Encounter

Kathleen Cox

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