Identification and Optimization of Pteridinone Toll-like Receptor 7 (TLR7) Agonists for the Oral Treatment of Viral Hepatitis
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- 作者：Paul A. Roethle ; Ryan M. McFadden ; Hong Yang ; Paul Hrvatin ; Hon Hui ; Michael Graupe ; Brian Gallagher ; Jessica Chao ; Joseph Hesselgesser ; Paul Duatschek ; Jim Zheng ; Bing Lu ; Daniel B. Tumas ; Jason Perry ; Randall L. Halcomb
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 26, 2013
- 年：2013
- 卷：56
- 期：18
- 页码：7324-7333
- 全文大小：456K
- 年卷期：v.56,no.18(September 26, 2013)
- ISSN：1520-4804
文摘
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 伪 (IFN-伪) and tumor necrosis factor 伪 (TNF-伪). 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.