3 research outputs found
Monitoring Drug Self-Aggregation and Potential for Promiscuity in Off-Target In Vitro Pharmacology Screens by a Practical NMR Strategy
A simple
NMR assay was applied to monitor the tendency of compounds
to self-aggregate in aqueous media. The observation of unusual spectral
trends as a function of compound concentration appears to be signatory
of the formation of self-assemblies. <sup>1</sup>H NMR resonances
of aggregating compounds were sensitive to the presence of a range
of molecular assemblies in solution including large molecular-size
entities, smaller multimers, and mixtures of assembled species. The
direct observation of aggregates via unusual NMR spectra also correlated
with promiscuous behavior of molecules in off-target in vitro pharmacology
assays. This empirical assay can have utility for predicting compound
promiscuity and should complement predictive methods that principally
rely on the computing of descriptors such as lipophilicity (cLogP)
and topological surface area (TPSA). This assay should serve as a
practical tool for medicinal chemists to monitor compound attributes
in aqueous solution and various pharmacologically relevant media,
as demonstrated herein
Compound Aggregation in Drug Discovery: Implementing a Practical NMR Assay for Medicinal Chemists
The
pharmaceutical industry has recognized that many drug-like
molecules can self-aggregate in aqueous media and have physicochemical
properties that skew experimental results and decisions. Herein, we
introduce the use of a simple NMR strategy for detecting the formation
of aggregates using dilution experiments that can be performed on
equipment prevalent in most synthetic chemistry departments. We show
that <sup>1</sup>H NMR resonances are sensitive to large molecular-size
entities and to smaller multimers and mixtures of species. Practical
details are provided for sample preparation and for determining the
concentrations of single molecule, aggregate entities, and precipitate.
The critical concentrations above which aggregation begins can be
found and were corroborated by comparisons with light scattering techniques.
Disaggregation can also be monitored using detergents. This NMR assay
should serve as a practical and readily available tool for medicinal
chemists to better characterize how their compounds behave in aqueous
media and influence drug design decisions
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