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Synthesis, structure-activity relationship studies and evaluation of a TLR 3/8/9 agonist and its analogues

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Abstract

A comprehensive SAR study of a putative TLR 3/8/9 agonist was conducted. Despite the excitement surrounding the potential of the first small molecule TLR3 agonist with a compound that additionally displayed agonist activity for TLR8 and TLR9, compound 1 displayed disappointing activity in our hands, failing to match the potency (EC50) reported and displaying only a low efficacy for the extent of stimulated NF-κB activation and release. The evaluation of >75 analogs of 1, many of which constitute minor modifications in the structure, failed to identify any that displayed significant activity and none that exceeded the modest activity found for 1.

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Acknowledgements

We gratefully acknowledge the financial support of NIH (CA042056, DLB) and Bristol Myers Squibb.

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Author notes

  1. These authors contributed equally: Anindya Sarkar, Anushka C. Galasiti Kankanamalage

Authors and Affiliations

  1. Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA

    Anindya Sarkar, Anushka C. Galasiti Kankanamalage & Dale L. Boger

  2. Bristol Myers Squibb Research & Development, 700 Bay Road, Redwood City, CA, 94063, USA

    Qian Zhang, Heng Cheng & Sanjeev Gangwar

  3. Bristol Myers Squibb Research & Development, PO Box 4000, Princeton, NJ, 08543, USA

    Prasanna Sivaprakasam, Joseph Naglich & Chunshan Xie

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  1. Anindya Sarkar
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  9. Dale L. Boger
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Correspondence to Dale L. Boger.

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Dedication: This article is dedicated to Professor Gary Grunewald, a treasured longtime friend and early colleague alongside which I had the pleasure of working for many years.

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Sarkar, A., Kankanamalage, A.C.G., Zhang, Q. et al. Synthesis, structure-activity relationship studies and evaluation of a TLR 3/8/9 agonist and its analogues. Med Chem Res 30, 1377–1385 (2021). https://doi.org/10.1007/s00044-021-02736-3

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  • DOI: https://doi.org/10.1007/s00044-021-02736-3

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