Publications by authors named "Geoffrey Stemp"

24 Publications

  • Page 1 of 1

Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders.

Bioorg Med Chem Lett 2011 Sep 30;21(18):5562-7. Epub 2011 Jun 30.

GlaxoSmithKline Medicine Research Centre, Via A. Fleming, 4, 37135 Verona, Italy.

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.086DOI Listing
September 2011

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

Identification of small molecule agonists of the motilin receptor.

Bioorg Med Chem Lett 2008 Dec 19;18(24):6423-8. Epub 2008 Oct 19.

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

High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
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http://dx.doi.org/10.1016/j.bmcl.2008.10.071DOI 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

Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.

Bioorg Med Chem Lett 2008 Oct 7;18(20):5698-700. Epub 2008 Aug 7.

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

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.010DOI Listing
October 2008

BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells.

Bioorg Med Chem Lett 2008 Feb 15;18(3):1022-6. Epub 2007 Dec 15.

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

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.020DOI Listing
February 2008

BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs).

Bioorg Med Chem Lett 2008 Feb 15;18(3):1011-6. Epub 2007 Dec 15.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.017DOI Listing
February 2008

BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character.

Bioorg Med Chem Lett 2008 Feb 15;18(3):1017-21. Epub 2007 Dec 15.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.019DOI Listing
February 2008

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands.

Bioorg Med Chem Lett 2007 Sep 30;17(18):5214-7. Epub 2007 Jun 30.

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

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.078DOI Listing
September 2007

A concise, convergent total synthesis of monocerin.

Org Biomol Chem 2006 Nov;4(22):4118-26

Department of Chemistry, Imperial College, London, SW7 2AY, UK.

A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core 2,3,5-trisubstituted tetrahydrofuran. End-game approaches based around intramolecular Heck chemistry revealed an interesting example of formal 6-endo cyclisation, the origin of which was probed using model substrates. The synthesis was ultimately completed by a strategy involving stepwise oxidative cleavage of the C3-ethenyl substituent.
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http://dx.doi.org/10.1039/b612256fDOI Listing
November 2006

Translational sciences-turning drug-like molecules into medicines.

Drug News Perspect 2006 Dec;19(10):659-63

On June 15, 2006, the Society for Medicines Research held a one-day meeting in Harlow, United Kingdom, entitled Translational Sciences-Turning Drug-like Molecules into Medicines. The meeting brought together speakers from Europe representing the pharmaceutical industry and provided an overview on some of the latest approaches in a range of areas such as predictive toxicology, translational biology, in vitro-in vivo extrapolation, pharmacokinetic/pharmacodynamic modeling, and the use of biomarkers and surrogate endpoints.
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December 2006

Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849.

Bioorg Med Chem Lett 2006 Sep 12;16(18):4872-8. Epub 2006 Jul 12.

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

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.061DOI Listing
September 2006

SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): discovery of antagonist SB-568849.

Bioorg Med Chem Lett 2006 Sep 12;16(18):4865-71. Epub 2006 Jul 12.

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

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.056DOI Listing
September 2006

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

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

Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796): a potent and selective dopamine D3 receptor antagonist.

J Med Chem 2003 11;46(23):4952-64

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

At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
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http://dx.doi.org/10.1021/jm030817dDOI Listing
November 2003

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

Directed dihydroxylation of cyclic allylic alcohols and trichloroacetamides using OsO4/TMEDA.

J Org Chem 2002 Nov;67(23):7946-56

Dyson Perrins Laboratory, South Parks Road, Oxford, OX1 3QY, UK.

The oxidation of a range of cyclic allylic alcohols and amides with OsO4/TMEDA is presented. Under these conditions, hydrogen bonding control leads to the (contrasteric) formation of the syn isomer in almost every example that was examined. Evidence for the bidentate binding of TMEDA to OsO4 is presented and a plausible mechanism described.
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http://dx.doi.org/10.1021/jo026161yDOI Listing
November 2002

Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.

J Neurosci 2002 Nov;22(21):9595-603

Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758043PMC
November 2002

Directed Dihydroxylation of Allylic Trichloroacetamides.

J Org Chem 1999 Apr;64(9):2980-2981

SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, U.K.

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http://dx.doi.org/10.1021/jo982468eDOI Listing
April 1999