Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors.

Basic Information

ID: ALA3797074

Journal: Bioorg Med Chem Lett

Title: Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors.

Authors: Zhao Z, Harrison ST, Schubert JW, Sanders JM, Polsky-Fisher S, Zhang NR, McLoughlin D, Gibson CR, Robinson RG, Sachs NA, Kandebo M, Yao L, Smith SM, Hutson PH, Wolkenberg SE, Barrow JC.

Abstract: A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.

CiteXplore: 27133481

DOI: 10.1016/j.bmcl.2016.03.095

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