Publications by authors named "Victor K Phuong"

7 Publications

  • Page 1 of 1

Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase.

Bioorg Med Chem Lett 2009 Dec 13;19(23):6548-51. Epub 2009 Oct 13.

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States.

A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. The synthesis, structure-activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.
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http://dx.doi.org/10.1016/j.bmcl.2009.10.033DOI Listing
December 2009

Anthranilic sulfonamide CCK1/CCK2 dual receptor antagonists II: tuning of receptor selectivity and in vivo efficacy.

Bioorg Med Chem Lett 2009 Nov 23;19(22):6376-8. Epub 2009 Sep 23.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

In the previous article we demonstrated how certain CCK2R-selective anthranilic amides could be structurally modified to afford high-affinity, selective CCK1R activity. We now describe our efforts at modulating and optimizing the CCK1R and CCK2R affinities aimed at producing compounds with good pharmacokinetics properties and in vivo efficacy in rat models of gastric acid and pancreatic amylase secretion.
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http://dx.doi.org/10.1016/j.bmcl.2009.09.065DOI Listing
November 2009

Anthranilic sulfonamide CCK1/CCK2 dual receptor antagonists I: discovery of CCKR1 selectivity in a previously CCKR2-selective lead series.

Bioorg Med Chem Lett 2009 Nov 23;19(22):6373-5. Epub 2009 Sep 23.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold.
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http://dx.doi.org/10.1016/j.bmcl.2009.09.064DOI Listing
November 2009

Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.

Bioorg Med Chem 2008 Apr 5;16(7):3917-25. Epub 2008 Feb 5.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Drug Discover, 3210 Merryfield Row, San Diego, CA 92121, USA.

A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
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http://dx.doi.org/10.1016/j.bmc.2008.01.059DOI Listing
April 2008

Synthesis and solid-phase purification of anthranilic sulfonamides as CCK-2 ligands.

Bioorg Med Chem Lett 2007 Dec 29;17(24):6905-9. Epub 2007 Sep 29.

Johnson & Johnson Pharmaceutical Research and Development, 3210 Merryfield Row, San Diego, CA 92121, USA.

A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.087DOI Listing
December 2007

Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.

J Med Chem 2006 Oct;49(21):6371-90

Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.
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http://dx.doi.org/10.1021/jm060590xDOI Listing
October 2006

Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists.

Bioorg Med Chem Lett 2004 Aug;14(16):4225-9

Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R.
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http://dx.doi.org/10.1016/j.bmcl.2004.06.032DOI Listing
August 2004