Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities

Kurimoto, Ayumu; Ogino, Tetsuhiro; Ichii, Shinji; Isobe, Yoshiaki; Tobe, Masanori; Ogita, Haruhisa; Takaku, Haruo; Sajiki, Hironao; Hirota, Kosaku; Kawakami, Hajime

doi:10.1016/j.bmc.2003.12.008

Cited by 76 publications

(82 citation statements)

References 31 publications

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“…An antedrug is defined as an active synthetic derivative that is designed to be readily metabolized to an inactive form upon entry into the systemic circulation. We have previously reported the discovery of adenine derivatives as a novel class of IFN-inducing agents (56)(57)(58)(59). Among these compounds, a representative compound has been identified as a novel class of TLR7 agonist (60).…”

Section: Discussionmentioning

confidence: 99%

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

Matsui

Tomizawa

Eiho

et al. 2012

The Journal of Immunology

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Triggering innate immune responses through TLRs is expected to be a novel therapeutic strategy for the treatment of allergic diseases. TLR agonists are able to modulate Th2 immune responses through undefined mechanisms. We investigated the mechanism of action of the suppression of Th2 immune responses with a novel antedrug TLR7 agonist. The antedrug is rapidly metabolized by plasma esterases to an acid with reduced activity to limit systemic responses. Topical administration of this compound inhibited features of the allergic airway inflammatory response in rat and murine allergic airways model. Type I IFN played a role in the suppression of Th2 cytokines produced from murine splenocytes. Inhibition of Th2 immune responses with the antedrug TLR7 agonist was shown to be via a type I IFN–dependent mechanism following short-term exposure to the compound, although there might be type I IFN–independent mechanisms following long-term exposure. We have demonstrated that local type I IFN signaling and plasmacytoid dendritic cells, but not Th1 immune responses, are required for in vivo efficacy against murine airway Th2-driven eosinophilia. Furthermore, migration of dendritic cell subsets into the lung was related to efficacy and is dependent on type I IFN signaling. Thus, the mechanism of action at the cytokine and cellular level involved in the suppression of Th2 allergic responses has been characterized, providing a potential new approach to the treatment of allergic disease.

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Section: Discussionmentioning

confidence: 99%

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

Matsui

Tomizawa

Eiho

et al. 2012

The Journal of Immunology

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“…Among the latter, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320; designated here as 1V136), has been shown to be a potent and specific TLR7 agonist (23). In the present study, we tested whether repeated low doses of this TLR7 ligand could induce refractoriness, or tolerance, to a TLR ligand challenge.…”

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confidence: 99%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.arthritis ͉ encephalomyelitis ͉ synthetic agonist

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“…Previously, it has been shown that TLR-7 agonists can elicit the release of antiviral cytokines in mice (21). In this study, we extend this analysis to include application of PK-PD modeling, using BHMA as a standard TLR agonist and IFN-␣ as a biomarker of effect.…”

Section: Discussionmentioning

confidence: 99%

“…BHMA was synthesized as described elsewhere (21). Unless stated otherwise, all other compounds were purchased from Sigma (Poole, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

Benson

Jongh²,

Duckworth

et al. 2010

Antimicrob Agents Chemother

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Recombinant alpha interferon (IFN-␣) is used in the treatment of hepatitis C virus (HCV)-infected patientsbut is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-␣ and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-␣ as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.An estimated 200 million people worldwide (39) are infected with hepatitis c virus (HCV). The virus replicates primarily in the liver, and 70% of those infected go on to develop chronic infection, with a further 20% progressing to serious liver disease (6). The current standard of care for HCV infection is treatment with pegylated alpha interferon (IFN-␣) combined with ribavirin; however, this treatment is effective for less than 50% of patients (26). Furthermore, significant side effects, including flu-like symptoms, depression, injection site reactions, and hemolytic anemia, are observed (10). The need to develop more available, better-tolerated, and more effective medicines is therefore clear. To this end, one of the areas of interest has been the targeting of IFN inducers (13, 18) and specifically Toll-like 7 receptor (TLR-7) agonists (9). The TLR family plays a critical role in the innate immune response via recognition of pathogen-associated molecular patterns (PAMPs). These are conserved and essential to viability. TLR-7 itself is thought to be endosomally located and to recognize and bind single-stranded RNA. This results in the induction of type I IFN production, including a robust IFN-␣ response, leading in turn to an antiviral effect. This response has been described previously as recognizing abnormal localization of nucleic acid rather than structures or motifs absent from the host (reference 7; for a review, see also reference 8).Although the hypothesis supporting the development of TLR-7 agonists as novel drugs appears to be sound, the behavior of a given drug in the in vivo system is often very hard to predict, leading to attrition due to lack of efficacy or safety concerns (20). As a means to address this issue quantitatively, biomarker and translational pharmacology approaches (25) and modeling-and simulation-based drug development (22, 37) are being explored as ways forward. To develop an improved understanding of translational pharmacology, biomarkers of efficacy that are present both in preclinical species and in humans would be highly valuable. A number of potential biomarkers of relevance for HCV have been reported previously (see, e.g., references 1, 16, and 38). Of these biomarkers, IFN-␣ is attractive as it is readily measurable in preclinical species and humans by commercia...

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Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities

Cited by 76 publications

References 31 publications

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

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

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

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