Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

Tran, Thien-Duc; Pryde, David C.; Jones, Peter; Adam, Fiona M.; Benson, Neil; Bish, Gerwyn; Calo, Frederick; Ciaramella, Guiseppe; Dixon, Rachel; Duckworth, Jonathan; Fox, David; Hay, Duncan; Hitchin, James R.; Horscroft, Nigel; Howard, Martin; Gardner, Iain; Jones, Hannah M.; Laxton, Carl; Parkinson, Tanya; Parsons, Gemma C.; Proctor, Katie; Smith, Mya C.; Smith, Nic; Thomas, Amy

doi:10.1016/j.bmcl.2011.02.092

Cited by 29 publications

(19 citation statements)

References 16 publications

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“…33 In addition, oral administration of TLR7 agonists have been tested clinically (using the prodrug TLR7 agonist ANA773) and preclinically for the treatment of hepatitis C virus infection. 34,35 In the present study we compared IT and PO administration of SM-276001 in the HM-1 model of metastatic ovarian cancer. Our data reveal that IT dosing led to the induction of TNFa, IL-6, KC and MIP-1a in BALF.…”

Section: Discussionmentioning

confidence: 99%

Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

Koga-Yamakawa

Dovedi

Murata

et al. 2012

Intl Journal of Cancer

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Topical TLR7 agonists such as imiquimod are highly effective for the treatment of dermatological malignancies; however, their efficacy in the treatment of nondermatological tumors has been less successful. We report that oral administration of the novel TLR7‐selective small molecule agonist; SM‐276001, leads to the induction of an inflammatory cytokine and chemokine milieu and to the activation of a diverse population of immune effector cells including T and B lymphocytes, NK and NKT cells. Oral administration of SM‐276001 leads to the induction of IFNα, TNFα and IL‐12p40 and a reduction in tumor burden in the Balb/c syngeneic Renca and CT26 models. Using the OV2944‐HM‐1 model of ovarian cancer which spontaneously metastasizes to the lungs following subcutaneous implantation, we evaluated the efficacy of intratracheal and oral administration of SM‐276001 in an adjuvant setting following surgical resection of the primary tumor. We show that both oral and intratracheal TLR7 therapy can reduce the frequency of pulmonary metastasis, and metastasis to the axillary lymph nodes. These results demonstrate that SM‐276001 is a potent selective TLR7 agonist that can induce antitumor immune responses when dosed either intratracheally or orally.

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Section: Discussionmentioning

confidence: 99%

Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

Koga-Yamakawa

Dovedi

Murata

et al. 2012

Intl Journal of Cancer

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“…Attempts have been made to recognize this liability early in a lead optimization stage and mitigate the potential of AO catalyzed metabolism at this stage. Several reports describing medicinal chemistry strategies to mitigate AO liabilities have been published recently (Magee et al, 2009;Jones et al, 2011;Linton et al, 2011;Tran et al, 2011;Pryde et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Dalvie

Sun²,

Xiang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, -stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (E LUMO )], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642-4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and E LUMO ). Overall, the structuremetabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structuremetabolism relationships of other AO substrates.

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“…In a previous study, oral administration of the TLR7 agonist, SM‐360320 was found to generate potent antitumor immune responses in carcinoembryonic antigen transgenic mice bearing MC38 colon adenocarcinoma cells 33. In addition, oral administration of TLR7 agonists have been tested clinically (using the prodrug TLR7 agonist ANA773) and preclinically for the treatment of hepatitis C virus infection 34, 35. In the present study we compared IT and PO administration of SM‐276001 in the HM‐1 model of metastatic ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Delay in receiving rheumatology care leads to long‐term harm

Bykerk¹,

Emery²

2010

Arthritis & Rheumatism

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In our study the effects of various factors in the reaction of chlorination and copolymerization of fatty acid wastes were investigated and optimum conditions were determined. The first purpose of this study is to investigate the electrochemical chlorination reaction of fatty acid wastes in the electrolysis of HCl, then to obtain composite materials by the products of this reaction, and finally to determine physicomechanical properties, heat resistance, and the effect of chloride to the fire strength of these composite materials. At that time the glycide ester of fatty acid (GEF) was synthesized and used as modificator for the determination of thermal and heat properties of composite materials. And the properties of composite materials that are obtained were compared. Styrene‐fatty acid copolymers (SFC) were also synthesized by interacting wasted product with styrene. Molecular weight of copolymer, number of carboxyl groups in its structure, its adhesion capability and thermal properties were investigated. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

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Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

Cited by 29 publications

References 16 publications

Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Delay in receiving rheumatology care leads to long‐term harm

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