3 research outputs found
Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2‑((6-Amino‑9<i>H</i>‑purin-9-yl)methyl)-5-methyl-3‑(<i>o</i>‑tolyl)quinazolin-4(3<i>H</i>)‑one (IC87114) and Its Conformationally Restricted Analogs
IC87114
[compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)Âmethyl)-5-methyl-3-(<i>o</i>-tolyl)Âquinazolin-4Â(3<i>H</i>)-one)] is
a potent PI3K inhibitor selective for the δ
isoform. As predicted by molecular modeling calculations, rotation
around the bond connecting the quinazolin-4Â(3<i>H</i>)-one
nucleus to the <i>o</i>-tolyl is sterically hampered, which
leads to separable conformers with axial chirality (i.e., atropisomers).
After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution,
we investigated how biological activity is influenced by axial chirality
and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in
the PI3Kδ assay. Conversely, the introduction of a methyl group
at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl
pendant to the quinazolin-4Â(3<i>H</i>)-one nucleus of both
a<i>S</i> and a<i>R</i> isomers of <b>1</b> had a critical effect on the inhibitory activity, indicating that
modulation of the conformational space accessible for the two bonds
departing from the central methylene considerably affects the binding
of compound <b>1</b> analogues to PI3Kδ enzyme
Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2‑((6-Amino‑9<i>H</i>‑purin-9-yl)methyl)-5-methyl-3‑(<i>o</i>‑tolyl)quinazolin-4(3<i>H</i>)‑one (IC87114) and Its Conformationally Restricted Analogs
IC87114
[compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)Âmethyl)-5-methyl-3-(<i>o</i>-tolyl)Âquinazolin-4Â(3<i>H</i>)-one)] is
a potent PI3K inhibitor selective for the δ
isoform. As predicted by molecular modeling calculations, rotation
around the bond connecting the quinazolin-4Â(3<i>H</i>)-one
nucleus to the <i>o</i>-tolyl is sterically hampered, which
leads to separable conformers with axial chirality (i.e., atropisomers).
After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution,
we investigated how biological activity is influenced by axial chirality
and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in
the PI3Kδ assay. Conversely, the introduction of a methyl group
at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl
pendant to the quinazolin-4Â(3<i>H</i>)-one nucleus of both
a<i>S</i> and a<i>R</i> isomers of <b>1</b> had a critical effect on the inhibitory activity, indicating that
modulation of the conformational space accessible for the two bonds
departing from the central methylene considerably affects the binding
of compound <b>1</b> analogues to PI3Kδ enzyme
Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases
Phosphodiesterase
4 (PDE4) is a key cAMP-metabolizing enzyme involved
in the pathogenesis of inflammatory disease, and its pharmacological
inhibition has been shown to exert therapeutic efficacy in chronic
obstructive pulmonary disease (COPD). Herein, we describe a drug discovery
program aiming at the identification of novel classes of potent PDE4
inhibitors suitable for pulmonary administration. Starting from a
previous series of benzoic acid esters, we explored the chemical space
in the solvent-exposed region of the enzyme catalytic binding pocket.
Extensive structural modifications led to the discovery of a number
of heterocycloalkyl esters as potent <i>in vitro</i> PDE4
inhibitors. (<i>S</i>*,<i>S</i>**)-<b>18e</b> and (<i>S</i>*,<i>S</i>**)-<b>22e</b>,
in particular, exhibited optimal <i>in vitro</i> ADME and
pharmacokinetics properties and dose-dependently counteracted acute
lung eosinophilia in an experimental animal model. The optimal biological
profile as well as the excellent solid-state properties suggest that
both compounds have the potential to be effective topical agents for
treating respiratory inflammatory diseases