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

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 <i>N</i>-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (<i>S</i>)-pentyloxy substitution at <i>C</i>-2 leading to the selection of GSK2245035 (<b>32</b>) as an intranasal development candidate. In human cell cultures, compound <b>32</b> resulted in suppression of Th2 cytokine responses to allergens, while <i>in vivo</i> 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 <b>32</b> of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals