Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection

Abstract

Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.

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

“…MS: calcd 371 (MH + ), measured 371 (MH + ). 1 3-(4-Fluorophenyl)-N-(m-tolyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (14). Yield: 33%.…”

“…Two types of distinct CpAMs (Figure ) have been advanced into clinical development. The type I CpAM is the heteroaryldihydropyrimidine (HAP) series of compounds, such as BAY 41-4109 and RG7907 (Linvencovir), which accelerate and misdirect the assembly of HBV core proteins to induce the formation of abnormal nucleocapsids, presumably followed by the protein degradation by host proteases . The type II CpAM is exemplified by NVR-3-778, JNJ-379, and ABI-H0731, which accelerates the assembly of core proteins to form empty capsids without the incorporation of pregenomic RNA (pgRNA).…”

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability

“…hydroxyl, methoxy, vinyl, ethynyl, cyano, and aldehyde (6a- (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)). The results indicated that these substitutions did not enhance the anti-HBV activity, suggesting that they were not effective at the protein-solvent interface.…”

“…Since the late 1990s, various chemotypes of compounds have been discovered to promote the assembly of Cp into aberrant or empty capsids, effectively inhibiting HBV replication. Examples of these compounds include heteroaryldihydropyrimidines (HAPs), [16][17][18][19][20] sulfamoylbenzamides (SBAs), 21 phenylpropenamides (PPAs), 22 and dibenzothiazepines (DBTs) 23 (Fig. 1).…”

“…These compounds incorporated rigid and polar fused bicyclic substituents at the C6 position, resulting in the discovery of the drug candidate RG7907, which exhibited potent anti-HBV activity (HepG.2.2.15 EC 50 = 6 nM), high metabolic stability, low hERG liability, and favorable animal pharmacokinetic profiles. 20 The successful development of RG7907 has served as an inspiration for our own structural optimization endeavors.…”