Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
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.
Learmonth
David A
DA
Laboratory of Chemistry, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal.
Bonifácio
Maria João
MJ
Soares-da-Silva
Patrício
P
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009574:Nitro Compounds