Catechol O-methyltransferase. 8. Structure-activity relationships for inhibition by 8-hydroxyquinolines

Abstract

A series of 5- and 7-substituted 8-hydroxyquinolines was evaluated as inhibitors of catechol O-methyltransferase (COMT, E.C. 2.1.1.6). The electronic character of the substituents in the 5 position appeared to have only a small effect if any on the inhibitory activity of these compounds. A significant factor which contributes to the inhibitory activity of these compounds appears to be the nature of the 7-substituent. The structure-activity relationship for this series of inhibitors is discussed relative to the nature of the enzymatic binding site.

Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity

“…catechol-O-methyl-transferase, logical interference aimed at prolonging the effect of NA and hence increasing cAMP and thermogenesis. Interestingly, there is evidence that the enzyme COMT can be inhibited by certain plant polyphenols, 10 and notably by those in the class of catechins which are found in high quantities in tea prior to its fermentation, i.e. tea.…”

Optimization of 8-Hydroxyquinolines as Inhibitors of CatecholO-Methyltransferase

“…Borchardt's exploration of 5-substituted 8-hydroxyquinolines showed that sulfonic acid (compound 5, Figure 2) had similar COMT inhibition to other electron withdrawing groups including chloro and nitro. 15 In designing additional binding interactions for the 8-hydroxyquinoline 4 (Figure 2) outside the metal chelating motif, modeling suggested substituents on either the 5-or 6-position would overlay with nitrocatechol pharmacophore 1 (Figure 2). We prepared both sulfone isomers 6 and 7 to guide future trajectories for exploration.…”

“…The clearance profile of both sulfonamides and sulfones is driven by phase II metabolism of the 8-hydroxy group; therefore, screening in hepatocytes was used to capture the impact of metabolism in vitro. Poor metabolic stability was observed with 7unsubstituted 8-hydroxyquinolines as evident by the high hepatocyte clearance for 15,16,and 17 (Table 3). A tight correlation between rat hepatocytes and in vivo clearance measured by PK studies was not evident; however, the hepatocyte screen proved useful for triaging compounds with high clearance.…”

Design, Synthesis and Photochemical Reactivation of Caged Prodrugs of 8-Hydroxyquinoline-Based Enzyme Inhibitors

“…[4][5][6][7][8][9][10][11][12][13] 5-Chloro-8-hydroxy-7-iodoquinoline (clioquinol, Chart 1) has been clinically used as an antifungal and antiprotozoal drug prior to the 1970's.…”

“…In our previous work, we reported that HQ 1 and its analogs (2)(3)(4)(5)(6)(7)(8) are potent and selective inhibitors (K i values= 0.16-29 µM) of an aminopeptidase from Aeromonas proteolytica (AAP) (EC 3.4.11.10), a dinuclear Zn 2+ peptidase (Chart 2). They have negligible inhibitory activities against leucine aminopeptidase (LAP), alkaline phosphatase, carboxypeptidase A, and carbonic anhydrase (CA) 31) (Chart 2).…”