2 research outputs found
Electrophilicity of Pyridazine-3-carbonitrile, Pyrimidine-2-carbonitrile, and Pyridine-carbonitrile Derivatives: A Chemical Model To Describe the Formation of Thiazoline Derivatives in Human Liver Microsomes
Certain
aromatic nitriles are well-known inhibitors of cysteine
proteases. The mode of action of these compounds involves the formation
of a reversible or irreversible covalent bond between the nitrile
and a thiol group in the active site of the enzyme. However, the reactivity
of these aromatic nitrile-substituted heterocycles may lead inadvertently
to nonspecific interactions with DNA, protein, glutathione, and other
endogenous components, resulting in toxicity and complicating the
use of these compounds as therapeutic agents. In the present study,
the intrinsic reactivity and associated structure–property
relationships of cathepsin K inhibitors featuring substituted pyridazines
[6-phenylpyridazine-3-carbonitrile, 6-(4-fluorophenyl)pyridazine-3-carbonitrile,
6-(4-methoxyphenyl)pyridazine-3-carbonitrile, 6-<i>p</i>-tolylpyridazine-3-carbonitrile], pyrimidines [5-<i>p</i>-tolylpyrimidine-2-carbonitrile, 5-(4-fluorophenyl)pyrimidine-2-carbonitrile],
and pyridines [5-<i>p</i>-tolylpicolinonitrile and 5-(4-fluorophenyl)picolinonitrile]
were evaluated using a combination of computational and analytical
approaches to establish correlations between electrophilicity and
levels of metabolites that were formed in glutathione- and <i>N</i>-acetylcysteine-supplemented human liver microsomes. Metabolites
that were characterized in this study featured substituted thiazolines
that were formed following rearrangements of transient glutathione
and <i>N</i>-acetylcysteine conjugates. Peptidases including
γ-glutamyltranspeptidase were shown to catalyze the formation
of these products, which were formed to lesser extents in the presence
of the selective γ-glutamyltranspeptidase inhibitor acivicin
and the nonspecific peptidase inhibitors phenylmethylsulfonyl fluoride
and aprotinin. Of the chemical series mentioned above, the pyrimidine
series was the most susceptible to metabolism to thiazoline-containing
products, followed, in order, by the pyridazine and pyridine series.
This trend was in keeping with the diminishing electrophilicity across
these series, as demonstrated by <i>in silico</i> modeling.
Hence, mechanistic insights gained from this study could be used to
assist a medicinal chemistry campaign to design cysteine protease
inhibitors that were less prone to the formation of covalent adducts
Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies
The hepatitis C virus (HCV) NS5B
replicase is a prime target for
the development of direct-acting antiviral drugs for the treatment
of chronic HCV infection. Inspired by the overlay of bound structures
of three structurally distinct NS5B palm site allosteric inhibitors,
the high-throughput screening hit anthranilic acid <b>4</b>,
the known benzofuran analogue <b>5</b>, and the benzothiadiazine
derivative <b>6</b>, an optimization process utilizing the simple
benzofuran template <b>7</b> as a starting point for a fragment
growing approach was pursued. A delicate balance of molecular properties
achieved via disciplined lipophilicity changes was essential to achieve
both high affinity binding and a stringent targeted absorption, distribution,
metabolism, and excretion profile. These efforts led to the discovery
of BMS-929075 (<b>37</b>), which maintained ligand efficiency
relative to early leads, demonstrated efficacy in a triple combination
regimen in HCV replicon cells, and exhibited consistently high oral
bioavailability and pharmacokinetic parameters across preclinical
animal species. The human PK properties from the Phase I clinical
studies of <b>37</b> were better than anticipated and suggest
promising potential for QD administration