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Bioorg Med Chem Lett. 2016 Jun 15;26(12):2952-2956. doi: 10.1016/j.bmcl.2016.03.095. Epub 2016 Apr 7.

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

Author information

1
Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
2
Chemistry, Modeling, and Informatics, Merck & Co., Inc., West Point, PA, United States.
3
Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, Merck & Co., Inc., West Point, PA, United States.
4
Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.

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.

KEYWORDS:

Catechol O-methyl transferase; Cognition; Schizophrenia

PMID:
27133481
DOI:
10.1016/j.bmcl.2016.03.095
[Indexed for MEDLINE]

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