Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

Thien-Duc Tran; David C Pryde; Peter Jones; Fiona M Adam; Neil Benson; Gerwyn Bish; Frederick Calo; Guiseppe Ciaramella; Rachel Dixon; Jonathan Duckworth; David N A Fox; Duncan A Hay; James Hitchin; Nigel Horscroft; Martin Howard; Iain Gardner; Hannah M Jones; Carl Laxton; Tanya Parkinson; Gemma Parsons; Katie Proctor; Mya C Smith; Nicholas Smith; Amy Thomas

doi:10.1016/j.bmcl.2011.02.092

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2389-93. doi: 10.1016/j.bmcl.2011.02.092. Epub 2011 Mar 16.

Affiliation

¹ Discovery Chemistry, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. thien.tran@pfizer.com

PMID: 21419626
DOI: 10.1016/j.bmcl.2011.02.092

Abstract

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.

MeSH terms

Administration, Oral
Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry*
Antiviral Agents / therapeutic use
Drug Design
Hepacivirus / drug effects*
Mice
Models, Animal
Purines / chemistry*
Purines / pharmacokinetics
Purines / therapeutic use
RNA Virus Infections / drug therapy*
Rats
Structure-Activity Relationship
Toll-Like Receptor 7 / agonists*
Toll-Like Receptor 7 / metabolism

Substances

Antiviral Agents
Purines
Toll-Like Receptor 7