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

Abstract

BackgroundThe 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.MethodsThe 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).ResultsFollowing 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%.ConclusionIn conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

Recombinant Human Interleukin-1 Receptor Antagonist in Severe Traumatic Brain Injury: A Phase II Randomized Control Trial

“…30 Furthermore, there is growing interest in the development of small-molecule CCR4 antagonists as potential therapies against systemic inflammatory conditions such as asthma. [31][32][33] It has also been suggested that targeting T-lymphocyte infiltration may improve outcome after TBI, based on an experimental model. 34 Whether the overall role of MDC in human TBI is beneficial or detrimental remains unknown.…”

Tumor microenvironment as a target of malignant gliomas treatment

“…Продолжается его изучение при других опухо-лях [10]. Другие препараты этой группы находятся в процес-се разработки [11]. Другим хемоаттрактантом, который может быть мишенью противоопухолевой терапии, является простагландин Е 2 (PgE2).…”

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

“…CCR3 and CCR4 act as receptors for a variety of chemokines including the eotaxins CCL5, CCL17, and CCL22, which play a role in asthma pathophysiology [23]. There is evidence that CCR3 inhibition may decrease inflammation, and CCR4 is believed to be able to recruit T H 2 cells to inflammatory sites [24]. CCR4 ligand binding induces the production and release of many cytokines [25] including granulocyte-macrophage colony-stimulating factor (GM-CSF) [26].…”

“…GSK2239633 [N-(3-[(3-[5-chlorothiophene-2-sulfonamido]-4-methoxy-1H-indazol-1-yl)methyl]benzyl)-2-hydroxy-2-methylpropanamide] is a potent CCR4 antagonist that acts by inhibiting CCR4-TARC (thymus and activation-regulated chemokine) binding and interrupting downstream signaling cascades [24]. The drug is currently in phase I trials.…”

“…There is evidence to suggest that CCR3 inhibition may decrease airway inflammation. CCR4 is believed to be able to recruit T H 2 cells to the site of inflammation [24]. …”