Synthesis of 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and Derivatives as Potent and Long-Acting Peripheral Inhibitors of Catechol-O-methyltransferase

• Published in: Journal of medicinal chemistry Vol. 45; no. 3; pp. 685 - 695
• Main Authors: Learmonth, David A, Vieira-Coelho, Maria A, Benes, Jan, Alves, Paula C, Borges, Nuno, Freitas, Ana P, Soares-da-Silva, Patrício
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 31.01.2002; Amer Chemical Soc
• Subjects: Acetophenones - chemical synthesis; Acetophenones - chemistry; Acetophenones - pharmacology; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Brain - drug effects; Brain - enzymology; Catechol O-Methyltransferase - metabolism; Catechol O-Methyltransferase Inhibitors; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Liver - drug effects; Liver - enzymology; Male; Medical sciences; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; SELECTIVE COMT INHIBITORS; METHYLATION; PHARMACOKINETICS; AMINO-ACIDS; TOLCAPONE; ADJUNCTS; LEVODOPA; Nitro compound; Rat; Liver; Central nervous system; Catechol O-methyltransferase; Neuroblastoma; Blood brain barrier; Diphenols; Structure activity relation; Chemical synthesis; Human; Enzyme; Transferases; Chain length; Rodentia; Benzene derivatives; Enzyme inhibitor; Bioavailability; Antiparkinson agent; In vitro; Long term; Intragastric administration; In vivo; Vertebrata; Mammalia; Ketophenols; Cell line; Methyltransferases; Animal; Homologous series; Pharmacokinetics; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0109964

A homologous series of novel nitro-catechol structures (7a−7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone) was found to exhibit the most potent and selective inhibition of peripheral COMT, with an inhibition profile more similar to entacapone 2 than tolcapone 1 (an equipotent peripheral and central inhibitor) but with much improved duration of action (7b, 70% inhibition and 2, 25% inhibition at 9 h after administration). The effects of structural modifications to 7b on COMT inhibitory profile were investigated, and it is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition. The introduction of the α-methylene group, the major structural difference between 7b and 1, would appear responsible for the observed enhancement in selectivity of peripheral COMT inhibition of 7b, which has more limited access to the brain than 1.