Publications by authors named "Alison J Ford"

12 Publications

  • Page 1 of 1

Identification of selective 8-(piperidin-4-yloxy)quinoline sulfone and sulfonamide histamine H receptor antagonists for use in allergic rhinitis.

Bioorg Med Chem Lett 2017 11 9;27(21):4914-4919. Epub 2017 Sep 9.

Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of potent, selective and long-acting quinoline-based sulfonamide human H histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
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http://dx.doi.org/10.1016/j.bmcl.2017.09.020DOI Listing
November 2017

Design of Phthalazinone Amide Histamine H Receptor Antagonists for Use in Rhinitis.

ACS Med Chem Lett 2017 May 21;8(5):577-581. Epub 2017 Apr 21.

Medicinal Chemistry, Respiratory Biology, R&D Platform Technology and Science, and Drug Metabolism and Pharmacokinetcs, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

The synthesis of potent amide-containing phthalazinone H histamine receptor antagonists is described. Three analogues , , and were equipotent with azelastine and were longer-acting in vitro. Amide had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430406PMC
May 2017

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists.

Bioorg Med Chem 2014 Aug 21;22(15):4298-311. Epub 2014 May 21.

Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD₇.₄ <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA₂ <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD₇.₄ (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.
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http://dx.doi.org/10.1016/j.bmc.2014.05.021DOI Listing
August 2014

Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing.

J Med Chem 2014 Jan 20;57(1):159-70. Epub 2013 Dec 20.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
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http://dx.doi.org/10.1021/jm401532gDOI Listing
January 2014

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

J Med Chem 2013 Mar 27;56(5):1946-60. Epub 2013 Feb 27.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
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http://dx.doi.org/10.1021/jm301572hDOI Listing
March 2013

In vitro pharmacological characterization of vilanterol, a novel long-acting β2-adrenoceptor agonist with 24-hour duration of action.

J Pharmacol Exp Ther 2013 Jan 6;344(1):218-30. Epub 2012 Nov 6.

Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

Vilanterol trifenatate (vilanterol) is a novel, long-acting β(2)-adrenoceptor (β(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize β(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the β(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for β(2)- over β(1)-AR and β(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective β(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).
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http://dx.doi.org/10.1124/jpet.112.198481DOI Listing
January 2013

Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation.

Bioorg Med Chem Lett 2012 Apr 7;22(8):2730-3. Epub 2012 Mar 7.

Department of Medicinal Chemistry, Respiratory CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom.

Synthesis and preliminary SAR of the N1 substituent of a novel series of indazole sulfonamide chemokine receptor 4 (CCR4) antagonist is reported. Compound 7r was identified for further development.
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http://dx.doi.org/10.1016/j.bmcl.2012.02.104DOI Listing
April 2012

The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group.

Bioorg Med Chem 2011 Oct 26;19(20):6026-32. Epub 2011 Aug 26.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
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http://dx.doi.org/10.1016/j.bmc.2011.08.043DOI Listing
October 2011

The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.

Bioorg Med Chem 2011 Jul 21;19(14):4192-201. Epub 2011 Jun 21.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
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http://dx.doi.org/10.1016/j.bmc.2011.05.064DOI Listing
July 2011

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.

J Med Chem 2010 Jun;53(11):4522-30

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
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http://dx.doi.org/10.1021/jm100326dDOI Listing
June 2010

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

J Med Chem 2009 Apr;52(8):2280-8

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
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http://dx.doi.org/10.1021/jm801016jDOI Listing
April 2009

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo.

Eur J Pharmacol 2005 Sep;519(3):237-45

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

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.
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http://dx.doi.org/10.1016/j.ejphar.2005.07.005DOI Listing
September 2005