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Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study

Anthony Cahn1*, Simon Hodgson1, Robert Wilson1, Jonathan Robertson1, Joanna Watson2, Misba Beerahee1, Steve C Hughes3, Graeme Young3, Rebecca Graves1, David Hall1, Sjoerd van Marle4 and Roberto Solari1

Author Affiliations

1 Medicines Discovery and Development, Gunnels Wood Road, Stevenage Herts SG1 2NY, UK

2 GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex UB11 1BT, UK

3 GlaxoSmithKline, Park Road, Ware SG12 0DP, UK

4 PRA International, Stationsweg 163, Zuidlaren 9741 GP, the Netherlands

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BMC Pharmacology and Toxicology 2013, 14:14  doi:10.1186/2050-6511-14-14

Published: 28 February 2013



The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy.


The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150–1500 mg (NCT01371812).


Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0–1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%.


In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

GSK2239633; CCR4; Microdose; Healthy