Synthesis and Biological Evaluation of a Novel Series of “Ortho-Nitrated” Inhibitors of Catechol-O-methyltransferase

• Published in: Journal of medicinal chemistry 2005-12, Vol.48 (25), p.8070-8078
• Main Authors: Learmonth, David A, Bonifácio, Maria João, Soares-da-Silva, Patrício
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacokinetics; Antidepressive Agents - pharmacology; Antiparkinson Agents - chemical synthesis; Antiparkinson Agents - pharmacokinetics; Antiparkinson Agents - pharmacology; Biological and medical sciences; Brain - drug effects; Brain - enzymology; Catechol O-Methyltransferase Inhibitors; Catechols - chemical synthesis; Catechols - pharmacokinetics; Catechols - pharmacology; Cell Line, Tumor; Humans; Liver - drug effects; Liver - enzymology; Medical sciences; Mice; Neuropharmacology; Nitro Compounds - chemical synthesis; Nitro Compounds - pharmacokinetics; Nitro Compounds - pharmacology; Pharmacology. Drug treatments; Rats; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0580454

Novel regioisomeric “ortho-nitrated” catechols related to the catechol-O-methyltransferase (COMT) inhibitors BIA 3-202 3 and BIA 3-335 4 were synthesized and biologically evaluated. Changing the position of the nitro group from the “classical” meta- to the ortho-position relative to the side-chain substituent of the nitrocatechol pharmacophore exerted profound effects on selectivity and duration of COMT inhibition. Alkylaryl compounds 7a − d possessed shorter duration of action than their regioisomers, but 7b displayed reversed selectivity over 3 at 3 and 6 h, exhibiting preferential central inhibition. In the amino-substituted series, ortho-nitrated regioisomer 14k was less peripherally selective than 4 and short-acting, whereas decahydroquinoline 14g displayed an unprecedented combination of long-acting and selective peripheral inhibition. 7b could provide a useful tool to probe the pharmacological utility of short-acting, centrally selective COMT inhibitors in the treatment of depression in Parkinsonian patients, and 14g represents a promising candidate for clinical evaluation as an adjunct to l-Dopa therapy.