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

Springer Science and Business Media LLC - Tập 30 - Trang 1377-1385 - 2021
Anindya Sarkar1, Anushka C. Galasiti Kankanamalage1, Qian Zhang2, Heng Cheng2, Prasanna Sivaprakasam3, Joseph Naglich3, Chunshan Xie3, Sanjeev Gangwar2, Dale L. Boger1
1Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, USA
2Bristol Myers Squibb Research & Development, Redwood City, USA
3Bristol Myers Squibb Research & Development, Princeton, USA

Tóm tắt

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.

Tài liệu tham khảo

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