Synthesis and Biological Evaluation of 8-Oxoadenine Derivatives as Toll-like Receptor 7 Agonists Introducing the Antedrug Concept

Abstract

Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC(50) 50 nM) and rapidly metabolized by human plasma (T(1/2) 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.

TLR7 Stimulation of APCs Results in Inhibition of IL-5 through Type I IFN and Notch Signaling Pathways in Human Peripheral Blood Mononuclear Cells

“…Stimulation of TLR7 modulates many of the end points associated with allergy in disease models including suppression of goblet cell hyperplasia, reduction in Th2 cytokines, lung eosinophilia, lung inflammation, and Ag-specific IgE (12)(13)(14)(15)(16)(17)(18). These data strongly support the concept of developing a TLR7 agonist to treat allergic disease, although current TLR7 agonists, used clinically in nonallergic indications, have side effects.…”

“…TLR7 antedrugs were rapidly metabolized in vivo (16,22) and short-term exposure of a TLR7 agonist was sufficient to induce IFN-a (22). Therefore, if the efficacy of an antedrug is linked to its ability to induce IFN-a, which itself has a short biological t 1/2 , then IFN-a has to induce effects that outlive its pharmacokinetic exposure.…”

“…In a bid to overcome this issue, AstraZeneca, in collaboration with Dainippon Sumitomo, has developed a series of 8-oxoadenine TLR7 antedrugs designed to be rapidly metabolized to a less active form upon entry into the circulation (16,22). Although these compounds have short-term lung exposure, it is sufficient to preferentially activate the IFN pathway leading to the production of IFN-a (22).…”

Mechanism of Action of Inhibition of Allergic Immune Responses by a Novel Antedrug TLR7 Agonist

“…The potency was greater than that observed on NF-kB-dependent reporter gene expression in TLR7-expressing HEK293 (Table I). To explore the factors playing a key role in the suppression, we determined whether type I IFN was involved in the inhibition of the Th2 cytokine production, as a TLR7 agonist is a powerful inducer of type I IFN (19). Results gained using splenocytes from IFN-a/bR 2/2 mice showed that, although rIFN-a inhibited IL-5, IL-13, and IFN-g production in murine splenocytes from wild-type mice in a dose-dependent manner, the suppression was completely lost in splenocytes from IFN-a/bR 2/2 mice (Fig.…”

“…Recently, we reported the synthesis and biological evaluation of antedrug TLR7 agonists, which are designed for rapid metabolism to a product with substantially reduced activity (19,20). Such compounds have the advantage over a metabolically stable TLR7 agonist by avoiding induction of potentially harmful systemic cytokine production.…”