Publications by authors named "Dongchuan Shi"

12 Publications

  • Page 1 of 1

Structure-activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists.

Bioorg Med Chem Lett 2011 May 5;21(10):2806-11. Epub 2011 Apr 5.

GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2011.03.107DOI Listing
May 2011

Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.

Bioorg Med Chem Lett 2011 Apr 15;21(8):2345-50. Epub 2011 Mar 15.

Discovery Medicinal Chemistry, Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, United States.

A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
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http://dx.doi.org/10.1016/j.bmcl.2011.02.077DOI Listing
April 2011

Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists.

ACS Med Chem Lett 2010 Oct 14;1(7):316-20. Epub 2010 May 14.

GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
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http://dx.doi.org/10.1021/ml100077xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007852PMC
October 2010

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.

ACS Med Chem Lett 2010 Sep 8;1(6):244-8. Epub 2010 Jun 8.

GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.
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http://dx.doi.org/10.1021/ml100105xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007837PMC
September 2010

2' biaryl amides as novel and subtype selective M1 agonists. Part I: Identification, synthesis, and initial SAR.

Bioorg Med Chem Lett 2010 Jun 17;20(12):3540-4. Epub 2010 May 17.

Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA.

Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.128DOI Listing
June 2010

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Bioorg Med Chem Lett 2010 Jun 17;20(12):3545-9. Epub 2010 May 17.

Discovery Research and Centers of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.127DOI Listing
June 2010

M3 muscarinic acetylcholine receptor antagonists: SAR and optimization of bi-aryl amines.

Bioorg Med Chem Lett 2009 Mar 4;19(6):1686-90. Epub 2009 Feb 4.

Centers of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
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http://dx.doi.org/10.1016/j.bmcl.2009.01.098DOI Listing
March 2009

Muscarinic acetylcholine receptor antagonists: SAR and optimization of tyrosine ureas.

Bioorg Med Chem Lett 2008 Oct 10;18(20):5481-6. Epub 2008 Sep 10.

Centers of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.

SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.020DOI Listing
October 2008

Discovery of biphenyl piperazines as novel and long acting muscarinic acetylcholine receptor antagonists.

J Med Chem 2008 Oct 18;51(19):5915-8. Epub 2008 Sep 18.

GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA.

A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
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http://dx.doi.org/10.1021/jm800935uDOI Listing
October 2008

Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.

J Med Chem 2008 Aug 5;51(16):4866-9. Epub 2008 Aug 5.

GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA.

High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
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http://dx.doi.org/10.1021/jm800634kDOI Listing
August 2008

Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles.

Bioorg Med Chem Lett 2008 Jul 20;18(13):3716-9. Epub 2008 May 20.

Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
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http://dx.doi.org/10.1016/j.bmcl.2008.05.058DOI Listing
July 2008

2-Aminomethyl piperidines as novel urotensin-II receptor antagonists.

Bioorg Med Chem Lett 2008 May 8;18(9):2860-4. Epub 2008 Apr 8.

Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.

A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
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http://dx.doi.org/10.1016/j.bmcl.2008.03.078DOI Listing
May 2008
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