Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma

Abstract

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial

“…Analyses of nasal allergic biomarkers revealed trends for a response to treatment. The observed reductions in selected Th2‐associated cytokines, chemokines and ECP post‐NAC are consistent with the known in vitro effect of IFN‐α to suppress Th2 responses and eosinophilia. In contrast to the effect on nasal symptoms, nasal biomarker data were not consistent for the two doses, likely reflecting the small sample size.…”

“…Therefore, the reductions in nasal symptoms measured up to 3 weeks post-treatment may have been due to an effect of locally induced IFN-a on mast cell numbers or mediator release39 rather than on adaptive immune responses.Analyses of nasal allergic biomarkers revealed trends for a response to treatment. The observed reductions in selected Th2associated cytokines, chemokines and ECP post-NAC are consistent with the known in vitro effect of IFN-a to suppress Th2 responses and eosinophilia23,[40][41][42] . In contrast to the effect on nasal symptoms, nasal biomarker data were not consistent for the two doses, likely reflecting the small sample size.Exposure to allergen is thought to be important for TLR7induced immunomodulatory changes.…”

“…23 The immunomodulatory potential of GSK2245035 was demonstrated in vitro where it reduced IL-5 and IL-13 and enhanced secretion of IL-10 and IFN-c, in cultures of peripheral blood mononuclear cells from donors with allergic rhinitis (AR). 23 Pharmacological assessment in healthy volunteers and participants with AR indicated that intranasal (i.n.) administration of GSK2245035 results in a dose-dependent activation of TLR7-mediated signalling in the upper airways.…”

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…Among the 8-oxoadenine family, Biggadike et al prepared derivatives bearing saturated oxygen or nitrogen heterocycles as N-9 substituting group [116]. To treat allergic asthma, GSK2245035 (24) is selected as intranasal candidate ( Fig.…”

8‐Oxo‐7,8‐dihydroadenine and 8‐Oxo‐7,8‐dihydroadenosine—Chemistry, Structure, and Function in RNA and Their Presence in Natural Products and Potential Drug Derivatives

“…Substitution at the 2-position of 8-oxoAde has led to al ibrary of small molecules with potent bioactivity in the treatment of chronic hepatitis Cv irus (HCV),s pecifically,i nterferon-alpha (IFN-a)i nducing activity with good bioavailability. Onen otable example was reported by Biggake et al recently,bydeveloping an 8-oxoAde derivative that can be delivered via intranasal doses, [79] [found to functionasaT oll-like receptor 7a gonist (TLR7)]. Over 90 derivatives have been reported over the years and the best hits have displayed more potency than imiquimod (clinically used in the United States as ap otent IFN inducer with serious side-effects).…”