Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists.

In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.

2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus.

A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J.

Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists.

The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48.

Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B.

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug.

Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus.

Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists.

Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response.

Unlabelled: Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients.

In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.

TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent.

In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.

The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.

Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors.

Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC(50) of 64nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice.