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

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.

SUBMITTER: Sarkar A

PROVIDER: S-EPMC8372028 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Sarkar Anindya A Galasiti Kankanamalage Anushka C AC Zhang Qian Q Cheng Heng H Sivaprakasam Prasanna P Naglich Joseph J Xie Chunshan C Gangwar Sanjeev S Boger Dale L DL

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 20210518 7

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, ...[more]

PMID: 34421287

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