Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.
Liqi HeMeng Yao ZhangMatthew CoxQian ZhangAndrew F DonnellYong ZhangChristine TarbyPatrice GillMurugaiah A M SubbaiahThangeswaran RamarMaheswara ReddyVijaya PuttapakaYi-Xin LiPrasanna SivaprakasamDavid CrittonDawn MulliganChunshan XieRadha RamakrishnanJignesh NagarShailesh DudhgaonkarAnwar MurtazaMartins S OderindeGary L SchievenArvind MathurAshvinikumar V GavaiGregory ViteSanjeev GangwarYam B PoudelPublished in: ACS medicinal chemistry letters (2024)
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.