title: Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis.
abstract: Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.
authors: Departments of †Medicinal Chemistry, ‡Clinical Virology, §Drug Metabolism, ∥Biology, and ⊥Structural Chemistry, Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors: Paul A
authors: PA
authors: Roethle
authors: Ryan M
authors: RM
authors: McFadden
authors: Hong
authors: H
authors: Yang
authors: Paul
authors: P
authors: Hrvatin
authors: Hon
authors: H
authors: Hui
authors: Michael
authors: M
authors: Graupe
authors: Brian
authors: B
authors: Gallagher
authors: Jessica
authors: J
authors: Chao
authors: Joseph
authors: J
authors: Hesselgesser
authors: Paul
authors: P
authors: Duatschek
authors: Jim
authors: J
authors: Zheng
authors: Bing
authors: B
authors: Lu
authors: Daniel B
authors: DB
authors: Tumas
authors: Jason
authors: J
authors: Perry
authors: Randall L
authors: RL
authors: Halcomb
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D011621:Pteridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D011621:Pteridines; D051199:Toll-Like Receptor 7