4 research outputs found
Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1
We disclose the discovery and X-ray
cocrystal data of potent, selective
quinazoline inhibitors of PDE1. Inhibitor (<i>S</i>)-<b>3</b> readily attains free plasma concentrations above PDE1 IC<sub>50</sub> values and has restricted brain access. The racemic compound <b>3</b> inhibits >75% of PDE hydrolytic activity in soluble samples
of human myocardium, consistent with heightened PDE1 activity in this
tissue. These compounds represent promising new tools to probe the
value of PDE1 inhibition in the treatment of cardiovascular disease
Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1
We disclose the discovery and X-ray
cocrystal data of potent, selective
quinazoline inhibitors of PDE1. Inhibitor (<i>S</i>)-<b>3</b> readily attains free plasma concentrations above PDE1 IC<sub>50</sub> values and has restricted brain access. The racemic compound <b>3</b> inhibits >75% of PDE hydrolytic activity in soluble samples
of human myocardium, consistent with heightened PDE1 activity in this
tissue. These compounds represent promising new tools to probe the
value of PDE1 inhibition in the treatment of cardiovascular disease
Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes
Acetyl-CoA
carboxylase (ACC) inhibitors offer significant potential
for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis,
and cancer. However, the identification of tool compounds suitable
to test the hypothesis in human trials has been challenging. An advanced
series of spirocyclic ketone-containing ACC inhibitors recently reported
by Pfizer were metabolized in vivo by ketone reduction, which complicated
human pharmacology projections. We disclose that this metabolic reduction
can be greatly attenuated through introduction of steric hindrance
adjacent to the ketone carbonyl. Incorporation of weakly basic functionality
improved solubility and led to the identification of <b>9</b> as a clinical candidate for the treatment of T2DM. Phase I clinical
studies demonstrated dose-proportional increases in exposure, single-dose
inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry
consistent with increased whole-body fatty acid oxidation. This demonstration
of target engagement validates the use of compound <b>9</b> to
evaluate the role of DNL in human disease
Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition
PF-06651600,
a newly discovered potent JAK3-selective inhibitor,
is highly efficacious at inhibiting γc cytokine signaling, which
is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison
of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition,
in relevant immune cells to a level that could not be achieved previously
without such potency and selectivity. <i>In vitro</i>, PF-06651600
inhibits Th1 and Th17 cell differentiation and function, and <i>in vivo</i> it reduces disease pathology in rat adjuvant-induced
arthritis as well as in mouse experimental autoimmune encephalomyelitis
models. Importantly, by sparing JAK1 function, PF-06651600 selectively
targets γc cytokine pathways while preserving JAK1-dependent
anti-inflammatory signaling such as the IL-10 suppressive functions
following LPS treatment in macrophages and the suppression of TNFα
and IL-1β production in IL-27-primed macrophages. Thus, JAK3-selective
inhibition differentiates from pan-JAK or JAK1 inhibition in various
immune cellular responses, which could potentially translate to advantageous
clinical outcomes in inflammatory and autoimmune diseases