4 research outputs found
Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor
The
design and synthesis of potent, tripeptidic acylsulfonamide
inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl
amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond
between the polarized C–H of the CHF<sub>2</sub> moiety and
the backbone carbonyl of Leu135 of the enzyme. Structure–activity
relationship studies indicate that this H-bond enhances enzyme inhibitory
potency by 13- and 17-fold compared to the CH<sub>3</sub> and CF<sub>3</sub> analogues, respectively, providing insight into the deployment
of this unique amino acid
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
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described.
This compound incorporates a cyclopropylÂacylsulfonamide moiety
that was designed to improve the potency of carboxylic acid prototypes
through the introduction of favorable nonbonding interactions within
the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties
including potency and pharmacokinetics (PK). This was achieved through
modulation of the P2* subsite of the inhibitor which identified the
isoquinoline ring system as a key template for improving PK properties
with further optimization achieved through functionalization. A methoxy
moiety at the C6 position of this isoquinoline ring system proved
to be optimal with respect to potency and PK, thus providing the clinical
compound <b>35</b> which demonstrated antiviral activity in
HCV-infected patients
Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
The
discovery of a back-up to the hepatitis C virus NS3 protease inhibitor
asunaprevir (<b>2</b>) is described. The objective of this work
was the identification of a drug with antiviral properties and toxicology
parameters similar to <b>2</b>, but with a preclinical pharmacokinetic
(PK) profile that was predictive of once-daily dosing. Critical to
this discovery process was the employment of an ex vivo cardiovascular
(CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation
of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity
relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications
at the P1 site, while potency gains were found with small, but rationally
designed structural changes to P4. Additional modifications at P3
were required to optimize the CV profile, and these combined SARs
led to the discovery of BMS-890068 (<b>29</b>)