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.

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.

Structure elucidation and spectroscopic analysis of photodegradants of the anti-rhinitis drug fluticasone furoate.

Fluticasone furoate is a novel glucocorticoid receptor agonist marketed as a treatment for seasonal and perennial allergic rhinitis. Forced degradation of fluticasone furoate under conditions of light led to a number of degradation products, the structures of which were elucidated using mass spectrometry and a range of one and two-dimensional NMR experiments. Three structures were derived, including two which involved a rearrangement of the steroid ring A to give cross-linked degradation products. The results demonstrate the applicability of a previously observed mechanism of photodegradation to fluticasone furoate.