Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus.

Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.

Small molecule approaches to treat autoimmune and inflammatory diseases (Part II): Nucleic acid sensing antagonists and inhibitors.

Nucleic acid sensing pathways play an important role in the innate immune system, protecting hosts against infections. However, a large body of evidence supports a close association between aberrant activation of those pathways and autoimmune and inflammatory diseases. Part II of the digest series on small molecule approaches to autoimmune and inflammatory diseases concentrates on recent advances with respect to small molecule antagonists or inhibitors of the nucleic acid sensing pathways, including endosomal TLRs, NLRP3 inflammasome and cGAS-STING.

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization.

RG7834 is a potent, orally bioavailable small-molecule inhibitor of hepatitis B virus (HBV) gene expression that belongs to the dihydroquinolizinone (DHQ) chemical class and uniquely blocks production of both viral DNA and antigens. In this study, we used DHQ compounds as tools in a compound-based adaptation version of the yeast three-hybrid screen to identify the cognate cellular protein targets, the non-canonical poly(A) RNA polymerase associated domain containing proteins 5 and 7 (PAPD5 and PAPD7). Interaction with RG7834 was mapped to the catalytic domains of the two cellular enzymes. The role of PAPD5 and PAPD7 in HBV replication was confirmed by oligonucleotide-mediated knockdown studies that phenocopied the result seen with RG7834-treated HBV-infected hepatocytes. The greatest effect on HBV gene expression was seen when PAPD5 and PAPD7 mRNAs were simultaneously knocked down, suggesting that the two cellular proteins play a redundant role in maintaining HBV mRNA levels. In addition, as seen previously with RG7834 treatment, PAPD5 and PAPD7 knockdown led to destabilization and degradation of HBV mRNA without impacting production of viral RNA transcripts. Conclusion: We identify PAPD5 and PAPD7 as cellular host factors required for HBV RNA stabilization and as therapeutic targets for the HBV cure.

Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action.

Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.

Discovery of Small Molecule Therapeutics for Treatment of Chronic HBV Infection.

The chronic infection of hepatitis B virus (HBV) inflicts 250 million people worldwide representing a major public health threat. A significant subpopulation of patients eventually develop cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, none of the current standard therapies for chronic hepatitis B (CHB) result in a satisfactory clinical cure rate. Driven by a highly unmet medical need, multiple pharmaceutical companies and research institutions have been engaged in drug discovery and development to improve the CHB functional cure rate, defined by sustainable viral suppression and HBsAg clearance after a finite treatment. This Review summarizes the recent advances in the discovery and development of novel anti-HBV small molecules. It is believed that an improved CHB functional cure rate may be accomplished via the combination of molecules with distinct MoAs. Thus, certain molecules may evolve into key components of a suitable combination therapy leading to superior outcome of clinical efficacy in the future.

Discovery of potent and selective CDK8 inhibitors through FBDD approach.

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.

Diastereoselective three-component reactions of aryldiazoacetates with alcohols/water and alkynals: application to substituted enelactones.

Dirhodium acetate catalyzed three-component reactions of aryl diazoacetates, alcohols or water, and 2-alkynals are reported to afford ß-alkynyl α,ß-dihydroxyl acid esters in good yield with high diastereoselectivity. Synthetic utility of the reaction was demonstrated in the conversion of the versatile alkynyl functionality to other synthetically useful compounds, including efficient synthesis of 2-aryl-2,3-dihydroxyl enelactones.