2 research outputs found
Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype‑2 and -3 (mGlu<sub>2/3</sub>) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence
As
part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor
positive allosteric modulator (PAM) research, we performed structure–activity
relationship (SAR) studies around a series of group II mGlu PAMs.
Initial analogues exhibited weak activity as mGlu<sub>2</sub> receptor
PAMs and no activity at mGlu<sub>3</sub>. Compound optimization led
to the identification of potent mGlu<sub>2/3</sub> selective PAMs
with no in vitro activity at mGlu<sub>1,4–8</sub> or 45 other
CNS receptors. In vitro pharmacological characterization of representative
compound <b>44</b> indicated agonist-PAM activity toward mGlu<sub>2</sub> and PAM activity at mGlu<sub>3</sub>. The most potent mGlu<sub>2/3</sub> PAMs were characterized in assays predictive of ADME/T
and pharmacokinetic (PK) properties, allowing the discovery of systemically
active mGlu<sub>2/3</sub> PAMs. On the basis of its overall profile,
compound <b>74</b> was selected for behavioral studies and was
shown to dose-dependently decrease cocaine self-administration in
rats after intraperitoneal administration. These mGlu<sub>2/3</sub> receptor PAMs have significant potential as small molecule tools
for investigating group II mGlu pharmacology
Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP
A series of novel, potent antagonists of the inhibitor
of apoptosis
proteins (IAPs) were synthesized in a highly convergent and rapid
fashion (≤6 steps) using the Ugi four-component reaction as
the key step, thus enabling rapid optimization of binding potency.
These IAP antagonists compete with caspases 3, 7, and 9 for inhibition
by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding
constants) to several crucial members of the IAP family of cancer
pro-survival proteins to promote apoptosis, with a particularly unique
selectivity for melanoma IAP (ML-IAP). Experiments in cell culture
revealed powerful cancer cell growth inhibitory activity in multiple
(breast, ovarian, and prostate) cell lines with single agent toxicity
at low nanomolar levels against SKOV-3 human ovarian carcinoma cells.
Administration of the compounds to human foreskin fibroblast cells
revealed no general toxicity to normal cells. Furthermore, computational
modeling was performed, revealing key contacts between the IAP proteins
and antagonists, suggesting a structural basis for the observed potency