3 research outputs found
Enantiomeric Atropisomers Inhibit HCV Polymerase and/or HIV Matrix: Characterizing Hindered Bond Rotations and Target Selectivity
An anthranilic acid series of allosteric
thumb pocket 2 HCV NS5B
polymerase inhibitors exhibited hindered rotation along a covalent
bond axis, and the existence of atropisomer chirality was confirmed
by NMR, HPLC analysis on chiral supports, and computational studies.
A thorough understanding of the concerted rotational properties and
the influence exerted by substituents involved in this steric phenomenon
was attained through biophysical studies on a series of truncated
analogues. The racemization half-life of a compound within this series
was determined to be 69 min, which was consistent with a class 2 atropisomer
(intermediate conformational exchange). It was further found by X-ray
crystallography that one enantiomer of a compound bound to the intended
HCV NS5B polymerase target whereas the mirror image atropisomer was
able to bind to an unrelated HIV matrix target. Analogues were then
identified that selectively inhibited the former. These studies highlight
that atropisomer chirality can lead to distinct entities with specific
properties, and the phenomenon of atropisomerism in drug discovery
should be evaluated and appropriately managed
Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127)
Conformational restrictions of flexible
torsion angles were used
to guide the identification of new chemotypes of HCV NS5B inhibitors.
Sites for rigidification were based on an acquired conformational
understanding of compound binding requirements and the roles of substituents
in the free and bound states. Chemical bioisosteres of amide bonds
were explored to improve cell-based potency. Examples are shown, including
the design concept that led to the discovery of the phase III clinical
candidate deleobuvir (BI 207127). The structure-based strategies employed
have general utility in drug design
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