7 research outputs found
Potential Probiotic or Trigger of Gut Inflammation – The Janus-Faced Nature of Cannabidiol-Rich Cannabis Extract
Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants
The
discovery of potent and pan-genotypic HCV NS5A inhibitors faces
many challenges including the significant diversity among genotypes,
substantial potency shift conferred on some key resistance-associated
variants, inconsistent SARs between different genotypes and mutants,
and the lacking of models of inhibitor/protein complexes for rational
inhibitor design. As part of ongoing efforts on HCV NS5A inhibition
at Merck, we now describe the discovery of a novel series of chromane
containing NS5A inhibitors. SAR studies around the “Z”
group of the tetracyclic indole scaffold explored fused bicyclic rings
as alternates to the phenyl group of elbasvir (<b>1</b>, MK-8742)
and identified novel chromane and 2,3-dihydrobenzofuran derivatives
as “Z” group replacements offered good potency across
all genotypes. This effort, incorporating the C-1 fluoro substitution
at the tetracyclic indole core, led to the discovery of a new series
of NS5A inhibitors, such as compounds <b>14</b> and <b>25</b>–<b>28</b>, with significantly improved potency against
resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a
L31V. Compound <b>14</b> also showed reasonable PK exposures
in preclinical species (rat and dog)
Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions
We
describe the discovery of MK-6169, a potent and pan-genotype
hepatitis C virus NS5A inhibitor with optimized activity against common
resistance-associated substitutions. SAR studies around the combination
of changes to both the valine and aminal carbon region of elbasvir
led to the discovery of a series of compounds with substantially improved
potency against common resistance-associated substitutions in the
major genotypes, as well as good pharmacokinetics in both rat and
dog. Through further optimization of key leads from this effort, MK-6169
(<b>21</b>) was discovered as a preclinical candidate for further
development
Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms
We describe the research that led
to the discovery of compound <b>40</b> (ruzasvir, MK-8408),
a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with
a “flat” GT1 mutant profile. This NS5A inhibitor contains
a unique tetracyclic indole core while maintaining the imidazole–proline–valine
Moc motifs of our previous NS5A inhibitors. Compound <b>40</b> is currently in early clinical trials and is under evaluation as
part of an all-oral DAA regimen for the treatment of chronic HCV infection