Publications by authors named "Mervyn Thompson"

13 Publications

  • Page 1 of 1

The discovery and optimisation of benzazepine sulfonamide and sulfones as potent agonists of the motilin receptor.

Bioorg Med Chem Lett 2009 Nov 12;19(22):6452-8. Epub 2009 Sep 12.

Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG12NY, UK.

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
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http://dx.doi.org/10.1016/j.bmcl.2009.09.027DOI Listing
November 2009

Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate.

J Med Chem 2009 Feb;52(4):1180-9

Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK.

N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
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http://dx.doi.org/10.1021/jm801332qDOI Listing
February 2009

The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

Bioorg Med Chem Lett 2008 Dec 19;18(24):6429-36. Epub 2008 Oct 19.

Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.

Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
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http://dx.doi.org/10.1016/j.bmcl.2008.10.072DOI Listing
December 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

Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.

J Pharmacol Exp Ther 2007 Jun 28;321(3):1183-92. Epub 2007 Mar 28.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.
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http://dx.doi.org/10.1124/jpet.106.116657DOI Listing
June 2007

N-Tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl biaryl carboxamides as antagonists of TRPV1.

Bioorg Med Chem Lett 2006 Sep 27;16(17):4533-6. Epub 2006 Jun 27.

Neurology and GI Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.026DOI Listing
September 2006

Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development.

Bioorg Med Chem Lett 2006 Jun 31;16(12):3287-91. Epub 2006 Mar 31.

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

Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
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http://dx.doi.org/10.1016/j.bmcl.2006.03.030DOI Listing
June 2006

Identification of a potent and selective 5-HT1B receptor antagonist.

Bioorg Med Chem Lett 2005 Nov;15(21):4708-12

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

An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
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http://dx.doi.org/10.1016/j.bmcl.2005.07.085DOI Listing
November 2005

Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.

Bioorg Med Chem Lett 2005 Nov;15(21):4867-71

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

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
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http://dx.doi.org/10.1016/j.bmcl.2005.06.107DOI Listing
November 2005

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

Bioorg Med Chem Lett 2005 Feb;15(3):737-41

Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2004.11.030DOI Listing
February 2005

Evidence for a molecular mechanism of teratogenicity of SB-236057, a 5-HT1B receptor inverse agonist that alters axial formation.

Birth Defects Res A Clin Mol Teratol 2004 Oct;70(10):789-807

Department of Reproductive Toxicology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.

Background: SB-236057 is a potent skeletal teratogen in rodents and rabbits, producing axial and posterior somite malformations in cultured rat embryos. The compound shares some structural similarity to cyclopamine.

Methods: M13 phage display was used to identify amino acid motifs with binding affinity to SB-236057. A 10 microM SB-236057 solution was administered to cultured day 9 postcoitus rat embryos and real-time PCR was conducted at 6 hr posttreatment to evaluate early transcriptional response of axial development genes. Whole-mount in situ hybridization of selected transcripts was conducted on embryos at 48 hr post-compound administration. The rat-enhancer of split protein 1 (r-esp1) expression-functional characterization was done by transcriptional expression and morpholino antisense approaches.

Results: We identified several amino acid motifs that had high binding affinity to SB-236057-biotin conjugates, one with 100% sequence homology to a region of r-esp1, one of the Groucho homologs transcribed by the enhancer of split complex (En[spl]C). SB-236057 repressed expression of r-esp1 and members of the Notch-En[spl]C pathway. Goosecoid and HNF3-beta, both suspected to associate with Groucho proteins, were also responsive, although expression of another putative binding protein, engrailed-1 (en-1), and other en-1 pathway members was not affected. R-esp1 mRNA was localized along the axis and antisense inhibition produced similar somite malformations as SB-236057 did. At 48 hr post-SB-236057 or post-r-esp1 antisense administration, affected embryos demonstrated unchanged sonic hedgehog (shh) expression, however HNF3-beta expression was either absent, altered, or reduced.

Conclusions: We present experimental evidence that the mechanism of SB-236057 teratogenicity includes transcriptional alterations to the Notch1-En[spl] pathway. In addition, alterations in HNF3-beta expression were similar to those induced by cyclopamine. The relationships between r-esp1 with Notch1 and shh signaling pathways and potential mechanisms of SB-236057 teratogenicity are also discussed.
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http://dx.doi.org/10.1002/bdra.20076DOI Listing
October 2004

Discovery of small molecule antagonists of TRPV1.

Bioorg Med Chem Lett 2004 Jul;14(14):3631-4

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

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.
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http://dx.doi.org/10.1016/j.bmcl.2004.05.028DOI Listing
July 2004

The design of 8,8-dimethyl[1,6]naphthyridines as potential anticonvulsant agents.

Bioorg Med Chem Lett 2003 May;13(10):1627-9

Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.
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http://dx.doi.org/10.1016/s0960-894x(03)00288-9DOI Listing
May 2003