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Medicinal.Chem.AbrahamThomas
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Med Chem blog by Abraham Thomas
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Medicinal.Chem.AbrahamThomas | Med Chem blog by Abraham Thomas Menu Skip to content Home About Medicinal.Chem.AbrahamThomas Med Chem blog by Abraham Thomas Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists Posted on November 5, 2015 by abrahamthomas100 Standard Reply We report the design and synthesis of novel 5,6-diarylated pyridin-2(1 H )-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1 H )-one 18b as a lead compound with good potency (IC 50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor sys...
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