Imidazoquinolines with improved pharmacokinetic properties induce a high IFNα to TNFα ratio in vitro and in vivo.

ABSTRACT: TLR Agonists have promising activity in preclinical models of viral infection and cancer. However, clinical use is only in topical application. Systemic uses of TLR-ligands such as Resiquimod, have failed due to adverse effects that limited dose and thus, efficacy. This issue could be related to pharmacokinetic properties that include fast elimination leading to low AUC with simultaneously high c_max at relevant doses. The high c_max is associated with a sharp, poorly tolerated cytokine pulse, suggesting that a compound with a higher AUC/c_max-ratio could provide a more sustained and tolerable immune activation. Our approach was to design TLR7/8-agonist Imidazoquinolines intended to partition to endosomes via acid trapping using a macrolide-carrier. Thi

SUBMITTER: Keppler M 

PROVIDER: S-EPMC10319141 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature