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Publication Abstract from PubMed

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.,He L, Zhang MY, Cox M, Zhang Q, Donnell AF, Zhang Y, Tarby C, Gill P, Subbaiah MAM, Ramar T, Reddy M, Puttapaka V, Li YX, Sivaprakasam P, Critton D, Mulligan D, Xie C, Ramakrishnan R, Nagar J, Dudhgaonkar S, Murtaza A, Oderinde MS, Schieven GL, Mathur A, Gavai AV, Vite G, Gangwar S, Poudel YB ACS Med Chem Lett. 2024 Jan 9;15(2):189-196. doi: 10.1021/acsmedchemlett.3c00456. , eCollection 2024 Feb 8. PMID:38352849^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.