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

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    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

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    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
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