Publications by authors named "Tanya Coleman"

19 Publications

  • Page 1 of 1

Probabilistic orthology analysis of the ATP-binding cassette transporters: implications for the development of multiple drug resistance phenotype.

Drug Metab Dispos 2012 Jul 16;40(7):1397-402. Epub 2012 Apr 16.

Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK.

Drug transporters are rapidly becoming recognized as central to determining a chemical's fate within the body. This action is a double-edged sword, protecting the body from toxicants, but also potentially leading to reduced clinical efficacy of drugs through multiple drug resistance phenotype. To examine the interrelationship of this superfamily, we have constructed phylogenetic trees over an extended evolutionary distance representing each of the seven subfamilies. In addition, using protein sequences from species important in the design and evaluation of novel chemicals, namely human, macaque, rat, mouse, and dog, we have undertaken probabilistic orthology analysis to examine speciation probabilities within this phylogeny. These data allow us to accurately predict orthologous sequences across these species, an important confirmatory step with implications for cross-species extrapolation of data during drug safety testing. Finally, we present the first complete phylogeny for subfamilies within humans constructed using the entire coding sequences, at both the DNA and protein levels. We demonstrate for the first time that genes associated with the multiple drug resistance phenotype cluster separately from other genes within the same subfamily, suggestive of a conserved, fundamental, difference in these proteins. Such work may help guide future studies on the mechanisms underlying multiple drug resistance as well as the development of novel therapeutic approaches to mitigate against its development.
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http://dx.doi.org/10.1124/dmd.112.045062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382838PMC
July 2012

AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family.

Cancer Res 2012 Apr 27;72(8):2045-56. Epub 2012 Feb 27.

AstraZeneca Innovation Center China, Building 7, 898 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.

The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3034DOI Listing
April 2012

Breast cancer resistance protein BCRP (ABCG2)-mediated transepithelial nitrofurantoin secretion and its regulation in human intestinal epithelial (Caco-2) layers.

Eur J Pharmacol 2011 Dec 10;672(1-3):70-6. Epub 2011 Oct 10.

Epithelial Research Group, Institute of Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.

In order to determine the capacity and regulation of the breast cancer resistance protein (BCRP)-mediated transport in intact human intestinal epithelial monolayers (Caco-2) in which multiple ABC transporters are expressed, nitrofurantoin has been used as a selective transported substrate. Nitrofurantoin transepithelial secretion was confirmed in both human BCRP and mouse bcrp-transfected MDCKII epithelia, whereas no net transepithelial secretion was observed in native or human MDR1-MDCKII epithelia. Furthermore, nitrofurantoin transepithelial secretion by BCRP-MDCKII monolayers was inhibited by Ko143 (10 μM), but not verapamil (100 μM). In Caco-2 cells grown upon permeable supports, nitrofurantoin displayed a dose-dependent transepithelial secretion with an apparent Km=69.41 ± 22.3 μM and Vmax=14.03 ± 2.27 nmol/(cm(2).h). Net nitrofurantoin transepithelial secretion by Caco-2 epithelia was inhibited 92% by 10 μM Ko143. Regulation of expression and function of BCRP in Caco-2 epithelial monolayers was determined after 72-h pre-exposure of the monolayers to a number of potential inducing agents. Quantitative real-time PCR and Western blotting were used to correlate induction of BCRP transcript and protein levels with transport activity. 72-h pre-treatment with β-napthoflavone and rosiglitazone up-regulates BCRP mRNA and protein expression and transport of nitrofurantoin. Ko143-sensitive transepithelial secretion of the bi-substrate (MDR1/BCRP) prazosin was also increased in the presence of rosiglitazone. We conclude that nitrofurantoin may be used to unambiguously measure BCRP-mediated fluxes in Caco-2 epithelial layers. Since dynamic regulation of BCRP expression and function is retained, the Caco-2 cell-line is useful as a screen for drug-drug and drug-diet interactions mediated by BCRP.
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http://dx.doi.org/10.1016/j.ejphar.2011.10.004DOI Listing
December 2011

The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.

Xenobiotica 2011 Jul 9;41(7):519-29. Epub 2011 Apr 9.

Faculty of Health and Medical Sciences, Centre for Toxicology, University of Surrey, Surrey, UK.

The therapeutic class of HMG-CoA reductase inhibitors, the statins are central agents in the treatment of hypercholesterolaemia and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Although statin therapy is generally considered safe, a number of known adverse effects do occur, most commonly treatment-associated muscular pain. In vitro evidence also supports the potential for drug-drug interactions involving this class of agents, and to examine this a ligand-binding assay was used to determine the ability of six clinically used statins for their ability to directly activate the nuclear receptors pregnane X-receptor (PXR), farnesoid X-receptor (FXR) and constitutive androstane receptor (CAR), demonstrating a relative activation of PXR>FXR>CAR. Using reporter gene constructs, we demonstrated that this order of activation is mirrored at the transcriptional activation level, with PXR-mediated gene activation being pre-eminent. Finally, we described a novel regulatory loop, whereby activation of FXR by statins increases PXR reporter gene expression, potentially enhancing PXR-mediated responses. Delineating the molecular interactions of statins with nuclear receptors is an important step in understanding the full biological consequences of statin exposure. This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.
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http://dx.doi.org/10.3109/00498254.2011.569773DOI Listing
July 2011

Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series.

Bioorg Med Chem Lett 2011 Apr;21(8):2207-11

AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims, Cedex 2, France.

Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2011.03.009DOI Listing
April 2011

Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue.

Biopharm Drug Dispos 2011 May 17;32(4):210-21. Epub 2011 Mar 17.

Drug Metabolism and Pharmacokinetics, AstraZeneca Research and Development, Alderley Park, Macclesfield, UK.

A clear understanding of oral drug absorption is an important aspect of the drug development process. The permeability of drug compounds across intact sections of small intestine from numerous species, including man, has often been investigated using modified Ussing chambers. The maintenance of viable, intact tissue is critical to the success of this technique. This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross-species Ussing chamber studies. Electrical parameters (potential difference, mV; short-circuit current, µA.cm(-2) ; resistance, Ω.cm(2) ) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10(-6) ) for a training-set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco-2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeability values generated in rat and human jejunum correlate well (R(2) = 0.86), however the relationship between permeability in human tissue and Caco-2 cells was comparatively weak (R(2) = 0.58). Relating permeability to known human fraction absorbed (hFabs) values results in a remarkably similar relationship to both rat and human jejunum Papp values. It can be concluded that human jejunum sourced from pancreatoduodenectomy is a suitable source of tissue for Ussing chamber permeability investigations. The relationship between permeability and hFabs is comparable to results reported using alternative test compounds.
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http://dx.doi.org/10.1002/bdd.751DOI Listing
May 2011

Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

Comput Methods Programs Biomed 2011 Nov 23;104(2):81-92. Epub 2010 Oct 23.

School of Engineering, University of Warwick, Coventry CV4 7AL, UK.

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios.
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http://dx.doi.org/10.1016/j.cmpb.2010.08.018DOI Listing
November 2011

Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.

Bioorg Med Chem Lett 2010 Nov 16;20(21):6242-5. Epub 2010 Sep 16.

AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.

Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.100DOI Listing
November 2010

In silico and in vitro modeling of hepatocyte drug transport processes: importance of ABCC2 expression levels in the disposition of carboxydichlorofluroscein.

Drug Metab Dispos 2009 Feb 20;37(2):391-9. Epub 2008 Nov 20.

Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK.

The impact of transport proteins in the disposition of chemicals is becoming increasingly evident. Alteration in disposition can cause altered pharmacokinetic and pharmacodynamic parameters, potentially leading to reduced efficacy or overt toxicity. We have developed a quantitative in silico model, based upon literature and experimentally derived data, to model the disposition of carboxydichlorofluroscein (CDF), a substrate for the SLCO1A/B and ABCC subfamilies of transporters. Kinetic parameters generated by the in silico model closely match both literature and experimentally derived kinetic values, allowing this model to be used for the examination of transporter action in primary rat hepatocytes. In particular, we show that the in silico model is suited to the rapid, accurate determination of K(i) values, using 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) as a prototypical pan-ABCC inhibitor. In vitro-derived data are often used to predict in vivo response, and we have examined how differences in protein expression levels between these systems may affect chemical disposition. We show that ABCC2 and ABCC3 are overexpressed in sandwich culture hepatocytes by 3.5- and 2.3-fold, respectively, at the protein level. Correction for this in markedly different disposition of CDF, with the area under the concentration versus time curve and C(max) of intracellular CDF increasing by 365 and 160%, respectively. Finally, using kinetic simulations we show that ABCC2 represents a fragile node within this pathway, with alterations in ABCC2 having the most prominent effects on both the K(m) and V(max) through the pathway. This is the first demonstration of the utility of modeling approaches to estimate the impact of drug transport processes on chemical disposition.
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http://dx.doi.org/10.1124/dmd.108.022921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680525PMC
February 2009

Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines.

Bioorg Med Chem Lett 2008 Nov 27;18(21):5717-21. Epub 2008 Sep 27.

AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

Crystallographic studies of a range of 3-substituted anilinopyrimidine inhibitors of EphB4 have highlighted two alternative C-2 aniline conformations and this discovery has been exploited in the design of a highly potent series of 3,5-disubstituted anilinopyrimidines. The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.087DOI Listing
November 2008

Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.

Bioorg Med Chem Lett 2008 Oct 31;18(20):5609-13. Epub 2008 Aug 31.

Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.105DOI Listing
October 2008

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.

Bioorg Med Chem Lett 2007 Feb 22;17(4):916-20. Epub 2006 Nov 22.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.059DOI Listing
February 2007

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives.

Bioorg Med Chem Lett 2007 Feb 28;17(3):732-5. Epub 2006 Oct 28.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.078DOI Listing
February 2007

The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain.

Bioorg Med Chem Lett 2007 Jan 20;17(2):385-9. Epub 2006 Oct 20.

Department of Medicinal Chemistry and DMPK, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.041DOI Listing
January 2007

Identification of novel pyrazole acid antagonists for the EP1 receptor.

Bioorg Med Chem Lett 2006 Sep 14;16(18):4767-71. Epub 2006 Jul 14.

Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.086DOI Listing
September 2006

Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.

Bioorg Med Chem Lett 2006 Jul 11;16(14):3657-62. Epub 2006 May 11.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
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http://dx.doi.org/10.1016/j.bmcl.2006.04.073DOI Listing
July 2006

Discovery of novel biaryl heterocyclic EP1 receptor antagonists.

Bioorg Med Chem Lett 2006 May 28;16(10):2666-71. Epub 2006 Feb 28.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
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http://dx.doi.org/10.1016/j.bmcl.2006.02.014DOI Listing
May 2006

8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.

Bioorg Med Chem Lett 2005 Oct;15(19):4370-4

High Throughput Chemistry, Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex CM19 5AW, UK.

The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
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http://dx.doi.org/10.1016/j.bmcl.2005.06.042DOI Listing
October 2005

Identification of a novel series of selective 5-HT7 receptor antagonists.

Bioorg Med Chem Lett 2003 Mar;13(6):1055-8

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
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http://dx.doi.org/10.1016/s0960-894x(03)00077-5DOI Listing
March 2003