|
Inhibition of Catechol O-methyltransferase activity in SK-N-SH cells at a concentration of 100 nM
|
None
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Inhibition of Catechol O-methyltransferase activity in rat brain
|
None
|
12.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat brain at dose of 30 mg/kg determined at 0.5 hr after its administration
|
None
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat brain at dose of 30 mg/kg determined at 3 hr after its administration
|
None
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat brain at dose of 30 mg/kg determined at 9 hr after its administration
|
None
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat liver at dose of 30 mg/kg determined at 0.5 hr after its administration
|
None
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat liver at dose of 30 mg/kg determined at 1 hr after its administration
|
None
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat liver at dose of 30 mg/kg determined at 3 hr after its administration
|
None
|
86.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat liver at dose of 30 mg/kg determined at 6 hr after its administration
|
None
|
74.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat liver at dose of 30 mg/kg determined at 9 hr after its administration
|
None
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percent inhibition of Catechol O-methyltransferase activity in rat brain at dose of 30 mg/kg determined at 1 hr after its administration
|
None
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
percent inhibition of Catechol O-methyltransferase activity in rat brain at dose of 30 mg/kg determined at 6 hr after its administration
|
None
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.
Year : 2002
Volume : 45
Issue : 3
First Page : 685
Last Page : 695
Authors : Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, da-Silva PS.
Abstract : 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 alpha-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.
|
Percentage inhibitory activity against COMT at 100 nM in human neuroblastoma SK-N-SH cells
|
Homo sapiens
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 0.5h in homogenates of rat brain administered with 30mg/kg by Gastric tube
|
Rattus norvegicus
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 1h in homogenates of rat brain administered with 30mg/kg by Gastric tube
|
Rattus norvegicus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 3h in homogenates of rat brain administered with 30mg/kg by Gastric tube
|
Rattus norvegicus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 6h in homogenates of rat brain administered with 30 mg/kg by Gastric tube
|
Rattus norvegicus
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 9h in homogenates of rat brain administered with 30 mg/kg by Gastric tube
|
Rattus norvegicus
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 1h in homogenates of rat liver administered with 30 mg/kg by Gastric tube
|
Rattus norvegicus
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 6h in homogenates of rat liver administered with 30 mg/kg by Gastric tube
|
Rattus norvegicus
|
74.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 0.5h in homogenates of rat liver administered with 30mg/kg by Gastric tube
|
Rattus norvegicus
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 3h in homogenates of rat liver administered with 30 mg/kg by Gastric tube
|
Rattus norvegicus
|
86.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Percentage inhibitory activity against COMT for 9h in homogenates of rat liver administered with 30mg/kg by Gastric tube
|
Rattus norvegicus
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
Year : 2005
Volume : 48
Issue : 25
First Page : 8070
Last Page : 8078
Authors : Learmonth DA, Bonifácio MJ, Soares-da-Silva P.
Abstract : 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.
|
Inhibition of COMT in human SK-N-SH cells at 100 nM
|
Homo sapiens
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2004
Volume : 47
Issue : 25
First Page : 6207
Last Page : 6217
Authors : Learmonth DA, Palma PN, Vieira-Coelho MA, Soares-da-Silva P.
Abstract : A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
|
Inhibition of peripheral COMT in mouse liver at 30 mg/kg, po by gastric tube after 1 hr
|
Mus musculus
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2004
Volume : 47
Issue : 25
First Page : 6207
Last Page : 6217
Authors : Learmonth DA, Palma PN, Vieira-Coelho MA, Soares-da-Silva P.
Abstract : A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
|
Inhibition of central COMT in mouse brain at 30 mg/kg, po by gastric tube after 1 hr
|
Mus musculus
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2004
Volume : 47
Issue : 25
First Page : 6207
Last Page : 6217
Authors : Learmonth DA, Palma PN, Vieira-Coelho MA, Soares-da-Silva P.
Abstract : A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
|
Inhibition of peripheral COMT in mouse liver at 30 mg/kg, po by gastric tube after 6 hrs
|
Mus musculus
|
26.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2004
Volume : 47
Issue : 25
First Page : 6207
Last Page : 6217
Authors : Learmonth DA, Palma PN, Vieira-Coelho MA, Soares-da-Silva P.
Abstract : A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
|
Inhibition of central COMT in mouse brain at 30 mg/kg, po by gastric tube after 6 hrs
|
Mus musculus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling studies of a novel, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2004
Volume : 47
Issue : 25
First Page : 6207
Last Page : 6217
Authors : Learmonth DA, Palma PN, Vieira-Coelho MA, Soares-da-Silva P.
Abstract : A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatom-containing substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.
|
Inhibition of COMT in NMRI mouse liver homogenates assessed as metanephrine formation at 30 mg/kg, po measured after 6 hrs relative to control
|
Mus musculus
|
93.6
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2010
Volume : 53
Issue : 8
First Page : 3396
Last Page : 3411
Authors : Kiss LE, Ferreira HS, Torrão L, Bonifácio MJ, Palma PN, Soares-da-Silva P, Learmonth DA.
Abstract : Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.
|
Inhibition of COMT in Wistar rat liver homogenates assessed as metanephrine formation at 3 mg/kg, po measured after 3 hrs relative to control
|
Rattus norvegicus
|
66.6
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2010
Volume : 53
Issue : 8
First Page : 3396
Last Page : 3411
Authors : Kiss LE, Ferreira HS, Torrão L, Bonifácio MJ, Palma PN, Soares-da-Silva P, Learmonth DA.
Abstract : Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.
|
Inhibition of COMT in NMRI mouse liver homogenates assessed as metanephrine formation at 3 mg/kg, po measured after 3 hrs relative to control
|
Mus musculus
|
79.8
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase.
Year : 2010
Volume : 53
Issue : 8
First Page : 3396
Last Page : 3411
Authors : Kiss LE, Ferreira HS, Torrão L, Bonifácio MJ, Palma PN, Soares-da-Silva P, Learmonth DA.
Abstract : Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.
|
Inhibition of Dengue virus NS2B-NS3 protease expressed in Escherichia coli BL21 lambda (DE3) using Abz-NleKRRS-3-(NO2)Y as substrate at 50 uM preincubated for 15 mins before substrate addition measured up to 15 mins by spectrofluorimetry
|
Dengue virus
|
21.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases.
Year : 2011
Volume : 19
Issue : 24
First Page : 7318
Last Page : 7337
Authors : Nitsche C, Steuer C, Klein CD.
Abstract : The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K(i)-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
|
Inhibition of West Nile virus NS2B-NS3 protease expressed in Escherichia coli BL21 lambda (DE3) using Abz-GLKRGG-3-(NO2)Y as substrate at 50 uM preincubated for 15 mins before substrate addition measured up to 15 mins by spectrofluorimetry
|
West Nile virus
|
32.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases.
Year : 2011
Volume : 19
Issue : 24
First Page : 7318
Last Page : 7337
Authors : Nitsche C, Steuer C, Klein CD.
Abstract : The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K(i)-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
|
Inhibition of human thrombin using Boc-VPR-AMC as substrate at 25 uM preincubated for 15 mins before substrate addition measured up to 10 mins by spectrofluorimetry
|
Homo sapiens
|
21.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases.
Year : 2011
Volume : 19
Issue : 24
First Page : 7318
Last Page : 7337
Authors : Nitsche C, Steuer C, Klein CD.
Abstract : The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a K(i)-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.
|
Inhibition of Mycobacterium tuberculosis InhA at 80 uM using DD-CoA and NADH
|
Mycobacterium tuberculosis
|
47.0
%
|
|
Journal : J. Med. Chem.
Title : Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.
Year : 2016
Volume : 59
Issue : 9
First Page : 4121
Last Page : 4151
Authors : Ehrt C, Brinkjost T, Koch O.
Abstract : Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct selectivity patterns and the prediction of possible off-target effects. The identification of similarities between binding sites of various proteins is a useful approach to cope with those challenges. The main scope of this perspective is to describe applications of different protein binding site comparison approaches to outline their applicability and impact on molecular design. The article deals with various substantial application domains and provides some outstanding examples to show how various binding site comparison methods can be applied to promote in silico drug design workflows. In addition, we will also briefly introduce the fundamental principles of different protein binding site comparison methods.
|
Inhibition of human recombinant His-tagged soluble COMT expressed in Escherichia coli BL21 using aesculetin as substrate after 60 mins by microplate assay in presence of SAM
|
Homo sapiens
|
386.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry.
Year : 2016
Volume : 59
Issue : 10
First Page : 4664
Last Page : 4675
Authors : von Kleist L, Michaelis S, Bartho K, Graebner O, Schlief M, Dreger M, Schrey AK, Sefkow M, Kroll F, Koester H, Luo Y.
Abstract : Structurally related inhibitors of a shared therapeutic target may differ regarding potential toxicity issues that are caused by different off-target bindings. We devised a differential competition capture compound mass spectrometry (dCCMS) strategy to effectively differentiate off-target profiles. Tolcapone and entacapone are potent inhibitors of catechol-O-methyl transferase (COMT) for the treatment of Parkinson's disease. Tolcapone is also known for its hepatotoxic side effects even though it is therapeutically more potent than entacapone. Here, we identified 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) as a possible toxicity-causing off-target of tolcapone, and this protein is not bound by the less toxic COMT inhibitor entacapone. Moreover, two novel compounds from a focused library synthesized in-house, N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide and 5-(3,4-dihydroxy-5-nitrobenzylidene)-3-ethylthiazolidine-2,4-dione, were utilized to gain insight into the structure-activity relationships in binding to COMT and the novel off-target HIBCH. These compounds, especially N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide, could serve as starting point for the development of improved and more specific COMT inhibitors.
|
Pharmacokinetic parameters for Enctacpone after single oral administartion of 200 and 800 mg Entacapone tablets to volunteers.
|
Homo sapiens
|
65.0
%
|
|
Pharmacokinetic parameters for Enctacpone after single oral administartion of 200 and 800 mg Entacapone tablets to volunteers.
|
Homo sapiens
|
82.0
%
|
|
Title : DailyMed|setid=ad6a2b73-29d4-4ced-ba42-4c2ad1c5a1af | ENTACAPONE - entacapone tablet, film coated|Sun Pharma Global FZE
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-7.14
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of synthetic AcPHF6 peptide aggregation in pH 7.4 phosphate buffer assessed as reduction in fluorescence intensity at 50 uM and measured every minute over 2 hrs with 5 secs shaking prior to each reading by ThT fluorescence assay
|
None
|
60.3
%
|
|
Journal : Eur J Med Chem
Title : Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6.
Year : 2019
Volume : 167
First Page : 146
Last Page : 152
Authors : Silva T, Mohamed T, Shakeri A, Rao PPN, Soares da Silva P, Remião F, Borges F.
Abstract : Polyphenols like caffeic acid and its phenethyl ester have been associated with potent anti-aggregating activity. Accordingly, we screened a library of polyphenols and synthetic derivatives thereof for their capacity to inhibit tau-aggregation using a thioflavin T-based fluorescence method. Our results show that the nitrocatechol scaffold is required for a significant anti-aggregating activity, which is enhanced by introducing bulky substituents at the side chain. A remarkable increase in activity was observed for α-cyanocarboxamide derivatives 26-27. Molecular docking studies showed that the amide bond provides superior conformational stability in the steric zipper assembly of tau, which drives the increase in activity. We also found that derivatives 24-27 were potent chelators of copper(II) - a property of pharmacological significance in abnormal protein aggregation. These small molecules can provide promising leads to develop new drugs for tauopathies and AD. These findings open a new window on the repurposing of nitrocatechols beyond their established role as catechol-O-methyltransferase inhibitors.
|
Inhibition of COMT (unknown origin) in presence of AdoMet and Esculetin by reaction kinetic model based assay relative to control
|
Homo sapiens
|
60.0
nM
|
|
|
Inhibition of S-COMT in Wistar rat liver assessed as metanephrine formation preincubated for 20 mins followed by addition of adrenaline as substrate and SAM measured after 5 mins by chromatographic analysis
|
Rattus norvegicus
|
34.45
nM
|
|
Journal : J Med Chem
Title : Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.
Year : 2016
Volume : 59
Issue : 16
First Page : 7584
Last Page : 7597
Authors : Silva T, Mohamed T, Shakeri A, Rao PP, Martínez-González L, Pérez DI, Martínez A, Valente MJ, Garrido J, Uriarte E, Serrão P, Soares-da-Silva P, Remião F, Borges F.
Abstract : Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
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Inhibition of MB-COMT in Wistar rat brain assessed as metanephrine formation preincubated for 20 mins followed by addition of adrenaline as substrate and SAM measured after 15 mins by chromatographic analysis
|
Rattus norvegicus
|
3.47
nM
|
|
Inhibition of MB-COMT in Wistar rat brain assessed as metanephrine formation preincubated for 20 mins followed by addition of adrenaline as substrate and SAM measured after 15 mins by chromatographic analysis
|
Rattus norvegicus
|
3.02
nM
|
|
Journal : J Med Chem
Title : Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.
Year : 2016
Volume : 59
Issue : 16
First Page : 7584
Last Page : 7597
Authors : Silva T, Mohamed T, Shakeri A, Rao PP, Martínez-González L, Pérez DI, Martínez A, Valente MJ, Garrido J, Uriarte E, Serrão P, Soares-da-Silva P, Remião F, Borges F.
Abstract : Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.82
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.45
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.23
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.23
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of rat liver COMT using esculetin as substrate by fluorescence based spectrophotometry
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase.
Year : 2020
Volume : 30
Issue : 12
First Page : 127188
Last Page : 127188
Authors : Hitge R, Smit S, Petzer A, Petzer JP.
Abstract : Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol-O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson's disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC<sub>50</sub> values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC<sub>50</sub> value of 0.048 μM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC<sub>50</sub> value of 0.23 μM. The results indicated that the pyrazoline derivatives (IC<sub>50</sub> = 0.048-0.21 µM) are more potent COMT inhibitors than the chalcones (IC<sub>50</sub> = 0.14-0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC<sub>50</sub> values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.
