The tautomerism of neutral hypoxanthine and allopurinol in the gas
phase and in aqueous solution
has been examined by theoretical methods. The tautomeric
equilibrium in the gas phase was studied
from semiempirical and ab initio quantum mechanics (QM) and
also from density functional theory
(DFT) calculations. Electron correlation effects were included in
ab initio computations at the
Møller−Plesset level, and DFT calculations were carried out using
the Becke3−Lee−Yang−Parr
functional. The influence of the solvent was examined from
self-consistent reaction field calculations
performed with different continuum models. The results provide a
detailed picture of the
tautomerism of these biologically relevant compounds. Comparison
with available experimental
data provides support for the quality of results derived from
theoretical computations. Inspection
of the most stable tautomeric forms allows discussion of the functional
implications of tautomerism
for recognition and binding of these molecules to xanthine
oxidase.
The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure−activity relationships and structure−property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.
Oral PI3Kδ inhibitors such
as Idelalisib and Duvelisib have
shown efficacy as anticancer agents and Idelalisib has been approved
for the treatment of three B-cell cancers. However, Idelalisib has
a black box warning on its product label regarding the risks of fatal
and serious toxicities including hepatic toxicity, severe diarrhea,
colitis, pneumonitis, infections, and intestinal perforation. Some
of these side effects are mechanism-related and could hinder the development
of Idelalisib for less severe conditions. For respiratory diseases,
compounds administered by inhalation are delivered directly to the
site of action and may improve the therapeutic index of a drug, minimizing
undesired side effects. This work describes the discovery and optimization
of inhaled PI3Kδ inhibitors intended for the treatment of severe
asthma and COPD. Once the potency was in the desired range, efforts
were focused on identifying the particular physicochemical properties
that could translate into better lung retention. This medicinal chemistry
exercise led to the identification of LAS195319 as a candidate for
clinical development.
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
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