5 research outputs found
Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution
Given
the emergence of resistance observed for the current clinical-stage
hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for
new inhibitors with a higher barrier to resistance. We recently reported
our rational approach to the discovery of macrocyclic acylsulfonamides
as HCV protease inhibitors addressing potency against clinically relevant
resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor
complexes, we shed light on the complex structural mechanisms by which
the D168V and R155K residue mutations confer resistance to NS3 protease
inhibitors. Here, we disclose SAR investigation and ADME/PK optimization
leading to the identification of inhibitors with significantly improved
potency against the key resistant variants and with increased liver
partitioning
Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)
Combinations of direct acting antivirals (DAAs) that
have the potential
to suppress emergence of resistant virus and that can be used in interferon-sparing
regimens represent a preferred option for the treatment of chronic
HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside
inhibitors of HCV NS5B polymerase that inhibit replication in replicon
systems. Herein, we report the late-stage optimization of indole-based
inhibitors, which began with the identification of a metabolic liability
common to many previously reported inhibitors in this series. By use
of parallel synthesis techniques, a sparse matrix of inhibitors was
generated that provided a collection of inhibitors satisfying potency
criteria and displaying improved in vitro ADME profiles. āCassetteā
screening for oral absorption in rat provided a short list of potential
development candidates. Further evaluation led to the discovery of
the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated
antiviral activity in patients chronically infected with genotype
1 HCV
Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection
The development of interferon-free
regimens for the treatment of
chronic HCV infection constitutes a preferred option that is expected
in the future to provide patients with improved efficacy, better tolerability,
and reduced risk for emergence of drug-resistant virus. We have pursued
non-nucleoside NS5B polymerase allosteric inhibitors as combination
partners with other direct acting antivirals (DAAs) having a complementary
mechanism of action. Herein, we describe the discovery of a potent
follow-up compound (BI 207524, <b>27</b>) to the first thumb
pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype
1 HCV infected patients, BILB 1941 (<b>1</b>). Cell-based replicon
potency was significantly improved through electronic modulation of
the p<i>K</i><sub>a</sub> of the carboxylic acid function
of the lead molecule. Subsequent ADME-PK optimization lead to <b>27</b>, a predicted low clearance compound in man. The preclinical
profile of inhibitor <b>27</b> is discussed, as well as the
identification of a genotoxic metabolite that led to the discontinuation
of the development of this compound
Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV
A scaffold
replacement approach was used to identifying the pyridine series of
noncatalytic site integrase inhibitors. These molecules bind with
higher affinity to a tetrameric form compared to a dimeric form of
integrase. Optimization of the C6 and C4 positions revealed that viruses
harboring T124 or A124 amino acid substitutions are highly susceptible
to these inhibitors, but viruses having the N124 amino acid substitution
are about 100-fold less susceptible. Compound <b>20</b> had
EC<sub>50</sub> values <10 nM against viruses having T124 or A124
substitutions in IN and >800 nM in viruses having N124 substitions.
Compound <b>20</b> had an excellent in vitro ADME profile and
demonstrated reduced contribution of biliary excretion to in vivo
clearance compared to BI 224436, the lead compound from the quinoline
series of NCINIs
Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs
Optimization
of pyridine-based noncatalytic site integrase inhibitors (NCINIs)
based on compound <b>2</b> has led to the discovery of molecules
capable of inhibiting virus harboring N124 variants of HIV integrase
(IN) while maintaining minimal contribution of enterohepatic recirculation
to clearance in rat. Structureāactivity relationships at the
C6 position established chemical space where the extent of enterohepatic
recirculation in the rat is minimized. Desymmetrization of the C4
substituent allowed for potency optimization against virus having
the N124 variant of integrase. Combination of these lessons led to
the discovery of compound <b>20</b>, having balanced serum-shifted
antiviral potency and minimized excretion in to the biliary tract
in rat, potentially representing a clinically viable starting point
for a new treatment option for individuals infected with HIV