Siegfried Goldmann

Inhibition of murine cytomegalovirus and human cytomegalovirus by a novel non-nucleosidic compound in vivo

Novel non-nucleosidic compounds have recently been identified as potent inhibitors of the human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) in vitro. We have now investigated the antiviral activity of these compounds in MCMV-infected NOD/LtSz-scid/j mice that lack functional T, B and, in contrast to C.B-17/Icr scid/scid mice, natural killer cells, and represent a novel model for cytomegalovirus infection in immunocompromised hosts. BAY 38-4766 (3-hydroxy-2,2-dimethyl-N-[4(([5-(dimethylamino)-1-naphthyl]sulfonyl)amino)- phenyl]propanamide) was identified as the most potent representative of this class of antiviral compounds. Per os administration of BAY 38-4766 at dosages > or = 10 mg/kg body weight led to antiviral effects that were comparable to ganciclovir 9-(1,3-dihydroxy-2-propoxymethyl)-guanine (Cymevene) as measured by survival and levels of viral DNA in organs of infected mice. In order to assess the anti-HCMV activity of BAY 38-4766 in vivo, we used a model, in which HCMV-infected human cells were entrapped in hollow fibers and subsequently transplanted into immunodeficient mice. Using this model, we demonstrated antiviral activity of BAY 38-4766 similar to that of ganciclovir. We conclude that BAY 38-4766 shows potential as an anti-HCMV drug.

3-((R)-4-(((R)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on Clinical Candidate GLS4

The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues. After several rounds of modification, compound 58 (HEC72702), which had an (R)-morpholine-2-propionic acid at the C6 position of its dihydropyrimidine core ring, was found to display no induction of the CYP1A2, CYP3A4, or CYP2B6 enzyme at the high concentration of 10 μM. In particular, it demonstrated a good systemic exposure and high oral bioavailability and achieved a viral-load reduction greater than 2 log in a hydrodynamic-injected (HDI) HBV mouse model and has now been selected for further development.