|
Percent inhibition of protein concentration in bronchoalveolar lavage fluid (BALF) from actively sensitized Brown norway rats at 2 mg/kg
|
Rattus norvegicus
|
47.0
%
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Percent inhibition of eosinophil infiltration in the guinea pig at 30 uM/kg (ip)
|
Cavia porcellus
|
17.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.
Year : 2001
Volume : 11
Issue : 1
First Page : 33
Last Page : 37
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.
|
Ability to block the release of TNF-alpha in human monocytes
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biarylcarboxamide inhibitors of phosphodiesterase IV and tumor necrosis factor-
Year : 1997
Volume : 7
Issue : 6
First Page : 739
Last Page : 744
Authors : Chambers R, Marfat A, Cheng J, Cohan V, Damon D, Duplantier A, Hibbs T, Jenkinson T, Johnson K, Kraus K, Pettipher E, Salter E, Shirley J, Umland J
|
Inhibition of LPS stimulated TNF-alpha release in mice at 10 mg/kg
|
Mus musculus
|
59.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biarylcarboxamide inhibitors of phosphodiesterase IV and tumor necrosis factor-
Year : 1997
Volume : 7
Issue : 6
First Page : 739
Last Page : 744
Authors : Chambers R, Marfat A, Cheng J, Cohan V, Damon D, Duplantier A, Hibbs T, Jenkinson T, Johnson K, Kraus K, Pettipher E, Salter E, Shirley J, Umland J
|
Evaluated for antiinflammatory activity in the TPA induced ear inflammation model at a dose 1 mg/kg (25 ug)
|
Mus musculus
|
69.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors.
Year : 2002
Volume : 12
Issue : 4
First Page : 653
Last Page : 658
Authors : Andrés JI, Alonso JM, Díaz A, Fernández J, Iturrino L, Martínez P, Matesanz E, Freyne EJ, Deroose F, Boeckx G, Petit D, Diels G, Megens A, Somers M, Van Wauwe J, Stoppie P, Cools M, De Clerck F, Peeters D, de Chaffoy D.
Abstract : This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
|
Evaluated for antiinflammatory activity in the TPA induced ear inflammation model at a dose 2 mg/kg (50 ug)
|
Mus musculus
|
88.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors.
Year : 2002
Volume : 12
Issue : 4
First Page : 653
Last Page : 658
Authors : Andrés JI, Alonso JM, Díaz A, Fernández J, Iturrino L, Martínez P, Matesanz E, Freyne EJ, Deroose F, Boeckx G, Petit D, Diels G, Megens A, Somers M, Van Wauwe J, Stoppie P, Cools M, De Clerck F, Peeters D, de Chaffoy D.
Abstract : This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
|
Percent inhibition of arachidonic acid induced mouse ear edema after 30 uM/kg peroral pretreatment
|
Mus musculus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones.
Year : 2002
Volume : 45
Issue : 12
First Page : 2526
Last Page : 2533
Authors : Van der Mey M, Boss H, Couwenberg D, Hatzelmann A, Sterk GJ, Goubitz K, Schenk H, Timmerman H.
Abstract : Recently, we reported that 4-catechol-substituted cis-(+/-)-4a,5,6,7,8,8a-hexa- and cis-(+/-)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting materials, were resolved in a classical way by the formation of diastereomeric salts, and each was converted to optically active phthalazinone in an enantioselective manner. The absolute configuration of the (+)-enantiomer of cis-hexahydrophthalazinone (+)-12 was determined by X-ray crystallography. The carbon atoms at the 4a and 8a positions were found to have the S- and R-configuration, respectively. In the present series of hexa- and tetrahydrophthalazinones, stereoselectivity for PDE4 inhibition is observed; the cis-(+)-enantiomers of the phthalazinones display high inhibitory activity, whereas their (-)-counterparts exhibit only weak to moderate activity. It is likely that all cis-(+)-phthalazinones have a (4aS,8aR)-configuration and vice versa for the cis-(-)-analogues. In the current series, the N-adamantan-2-yl analogue (+)-14 shows the most potent inhibition of PDE4 (pIC(50) = 9.3); the corresponding (-)-enantiomer is 250-fold less active. In addition, the N-substituted tetrahydrophthalazinones under study were investigated for their in vivo antiinflammatory activities by examining the suppression of arachidonic acid (AA) induced mouse ear edema formation. In this assay analogues (+)-14 and (+)-15 were found to be potent antiinflammatory agents showing about 50% inhibition at 30 micromol/kg po.
|
Percent inhibition of arachidonic acid (AA) formation, induced mouse ear edema after pretreatment at a concentration of 30 umol/kg (po)
|
Mus musculus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones.
Year : 2002
Volume : 45
Issue : 12
First Page : 2520
Last Page : 2525
Authors : Van der Mey M, Boss H, Hatzelmann A, Van der Laan IJ, Sterk GJ, Timmerman H.
Abstract : The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFalpha release and show moderate potency against fMLP-stimulated production of ROS.
|
Inhibition of arachidonic acid (AA)-induced mouse ear edema after pretreatment with compound (1 h before AA) at a drug concentration of 30 umol/kg po.
|
Mus musculus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents.
Year : 2003
Volume : 46
Issue : 10
First Page : 2008
Last Page : 2016
Authors : Van der Mey M, Bommelé KM, Boss H, Hatzelmann A, Van Slingerland M, Sterk GJ, Timmerman H.
Abstract : In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC(50) = 7.0-8.7), whereas the pIC(50) values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30 micromol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.
|
Inhibition of phosphodiesterase type 4 isozyme (PDE4) from the U937 human cell line.
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors.
Year : 2000
Volume : 43
Issue : 25
First Page : 4850
Last Page : 4867
Authors : Burnouf C, Auclair E, Avenel N, Bertin B, Bigot C, Calvet A, Chan K, Durand C, Fasquelle V, Féru F, Gilbertsen R, Jacobelli H, Kebsi A, Lallier E, Maignel J, Martin B, Milano S, Ouagued M, Pascal Y, Pruniaux MP, Puaud J, Rocher MN, Terrasse C, Wrigglesworth R, Doherty AM.
Abstract : The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
|
Inhibition of phosphodiesterase 4 (PDE4) in human neutrophils
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones.
Year : 2001
Volume : 44
Issue : 16
First Page : 2523
Last Page : 2535
Authors : Van der Mey M, Hatzelmann A, Van Klink GP, Van der Laan IJ, Sterk GJ, Thibaut U, Ulrich WR, Timmerman H.
Abstract : A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC(50) = 9.7).
|
Inhibition of PDE4 in the cytosol of human neutrophils
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues.
Year : 2001
Volume : 44
Issue : 16
First Page : 2511
Last Page : 2522
Authors : Van der Mey M, Hatzelmann A, Van der Laan IJ, Sterk GJ, Thibaut U, Timmerman H.
Abstract : A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.
|
Inhibitory activity against Phosphodiesterase 4A (PDE4A) from human source expressed in Saccharomyces cerevisiae
|
None
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Inhibitory concentration against human PDE4A isoform using a construct representing the common region of spliced variants expressed as GST-fusion protein in Sf9 cells
|
None
|
38.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor.
Year : 2002
Volume : 12
Issue : 11
First Page : 1457
Last Page : 1461
Authors : Guay D, Hamel P, Blouin M, Brideau C, Chan CC, Chauret N, Ducharme Y, Huang Z, Girard M, Jones TR, Laliberté F, Masson P, McAuliffe M, Piechuta H, Silva J, Young RN, Girard Y.
Abstract : Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.
|
Inhibition of human Phosphodiesterase 4A isoform using construct representing the common region of spliced variants expressed as GST-fusion proteins in Sf9 cells.
|
None
|
38.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters.
Year : 2002
Volume : 12
Issue : 20
First Page : 3009
Last Page : 3013
Authors : Frenette R, Blouin M, Brideau C, Chauret N, Ducharme Y, Friesen RW, Hamel P, Jones TR, Laliberté F, Li C, Masson P, McAuliffe M, Girard Y.
Abstract : A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.
|
Inhibition of human Phosphodiesterase 4A from peripheral blood mononuclear cells
|
Homo sapiens
|
398.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor.
Year : 2002
Volume : 12
Issue : 2
First Page : 233
Last Page : 235
Authors : Hersperger R, Dawson J, Mueller T.
Abstract : The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC(50)=1.5nM) are described. The compound inhibited TNFalpha-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
|
Inhibition of human Phosphodiesterase 4B from peripheral blood mononuclear cells
|
Homo sapiens
|
288.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor.
Year : 2002
Volume : 12
Issue : 2
First Page : 233
Last Page : 235
Authors : Hersperger R, Dawson J, Mueller T.
Abstract : The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC(50)=1.5nM) are described. The compound inhibited TNFalpha-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
|
Inhibitory activity against Phosphodiesterase 4B (PDE4B) from rat source expressed in Saccharomyces cerevisiae
|
None
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Inhibitory activity against Phosphodiesterase 4C (PDE4C) from human source expressed in Saccharomyces cerevisiae
|
None
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Inhibition of human Phosphodiesterase 4C from peripheral blood mononuclear cells
|
Homo sapiens
|
813.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor.
Year : 2002
Volume : 12
Issue : 2
First Page : 233
Last Page : 235
Authors : Hersperger R, Dawson J, Mueller T.
Abstract : The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC(50)=1.5nM) are described. The compound inhibited TNFalpha-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
|
Inhibitory activity against Phosphodiesterase 4D (PDE4D) from human source expressed in Saccharomyces cerevisiae
|
None
|
79.0
nM
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Inhibition of human Phosphodiesterase 4D from peripheral blood mononuclear cells
|
Homo sapiens
|
63.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor.
Year : 2002
Volume : 12
Issue : 2
First Page : 233
Last Page : 235
Authors : Hersperger R, Dawson J, Mueller T.
Abstract : The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC(50)=1.5nM) are described. The compound inhibited TNFalpha-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
|
Tested for its ability to inhibit the hydrolysis of cAMP by human monocyte cytosol phosphodiesterase
|
None
|
360.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biarylcarboxamide inhibitors of phosphodiesterase IV and tumor necrosis factor-
Year : 1997
Volume : 7
Issue : 6
First Page : 739
Last Page : 744
Authors : Chambers R, Marfat A, Cheng J, Cohan V, Damon D, Duplantier A, Hibbs T, Jenkinson T, Johnson K, Kraus K, Pettipher E, Salter E, Shirley J, Umland J
|
Inhibition activity against human monocyte derived PDE4 catalytic activity (LPDE4)
|
None
|
95.0
nM
|
|
Inhibition activity against human monocyte derived PDE4 catalytic activity (LPDE4)
|
None
|
530.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
Year : 1998
Volume : 41
Issue : 6
First Page : 821
Last Page : 835
Authors : Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ.
Abstract : Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
|
Competition of [3H]rolipram binding sites in the central nervous system (HPDE4) in rat brain cytosol
|
None
|
120.0
nM
|
|
Competition of [3H]rolipram binding sites in the central nervous system (HPDE4) in rat brain cytosol
|
None
|
700.0
nM
|
|
Competition of [3H]rolipram binding sites in the central nervous system (HPDE4) in rat brain cytosol
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
Year : 1998
Volume : 41
Issue : 6
First Page : 821
Last Page : 835
Authors : Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ.
Abstract : Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
|
Inhibition of human Phosphodiesterase 4
|
Homo sapiens
|
73.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.
Year : 2001
Volume : 11
Issue : 1
First Page : 33
Last Page : 37
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.
|
Inhibition of rolipram binding to PDE4
|
Homo sapiens
|
38.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.
Year : 2001
Volume : 11
Issue : 1
First Page : 33
Last Page : 37
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.
|
Inhibition of human Phosphodiesterase 4
|
Homo sapiens
|
73.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 3: the synthesis and in vitro evaluation of derivatives with a hydrogen bond acceptor.
Year : 2002
Volume : 12
Issue : 1
First Page : 5
Last Page : 8
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Fattori R, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.
|
Inhibition of PDE4 from U937 monocytic cells
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Orally active PDE4 inhibitors with therapeutic potential.
Year : 2004
Volume : 14
Issue : 5
First Page : 1323
Last Page : 1327
Authors : Ochiai H, Ohtani T, Ishida A, Kishikawa K, Obata T, Nakai H, Toda M.
Abstract : Based on the successful results in the clinical trial of Ariflo, further optimization of the spatial arrangement of the three pharmacophores (carboxylic acid moiety, nitrile moiety and 3-cyclopentyl-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3.3.0]octane template instead of a cyclohexane template. As a result, 2a, 7a and 7b were found to be orally active and were predicted to have an improved therapeutic potential based on evaluation by cross-species and same-species comparisons. Structure-activity relationships (SARs) of these compounds are also discussed.
|
Inhibitory activity on human eosinophil phosphodiesterase 4.
|
None
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : 7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase.
Year : 1998
Volume : 41
Issue : 13
First Page : 2268
Last Page : 2277
Authors : Duplantier AJ, Andresen CJ, Cheng JB, Cohan VL, Decker C, DiCapua FM, Kraus KG, Johnson KL, Turner CR, UmLand JP, Watson JW, Wester RT, Williams AS, Williams JA.
Abstract : High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).
|
Inhibition of [3H]rolipram binding in human peripheral blood mononuclear cells
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor.
Year : 2002
Volume : 12
Issue : 2
First Page : 233
Last Page : 235
Authors : Hersperger R, Dawson J, Mueller T.
Abstract : The synthesis of a 6,8-disubstituted 1,7-naphthyridine 1 and its characterization as a potent and selective phosphodiesterase type 4D inhibitor (IC(50)=1.5nM) are described. The compound inhibited TNFalpha-release from human peripheral blood mononuclear cells and was orally active in a model of adjuvant-induced arthritis in rats.
|
Inhibition of rolipram binding to Phosphodiesterase 4
|
Homo sapiens
|
38.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 3: the synthesis and in vitro evaluation of derivatives with a hydrogen bond acceptor.
Year : 2002
Volume : 12
Issue : 1
First Page : 5
Last Page : 8
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Fattori R, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.
|
inhibition of cAMP-specific phosphodiesterase 4 (PDE4) was determined in cytosol from human neutrophils
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of cis-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual PDE3/PDE4 inhibitory agents.
Year : 2003
Volume : 46
Issue : 10
First Page : 2008
Last Page : 2016
Authors : Van der Mey M, Bommelé KM, Boss H, Hatzelmann A, Van Slingerland M, Sterk GJ, Timmerman H.
Abstract : In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC(50) = 7.0-8.7), whereas the pIC(50) values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30 micromol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.
|
Inhibitory activity against phosphodiesterase 4 carried out in the cytosol of human neutrophils
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis-tetra- and cis-hexahydrophthalazinones.
Year : 2002
Volume : 45
Issue : 12
First Page : 2526
Last Page : 2533
Authors : Van der Mey M, Boss H, Couwenberg D, Hatzelmann A, Sterk GJ, Goubitz K, Schenk H, Timmerman H.
Abstract : Recently, we reported that 4-catechol-substituted cis-(+/-)-4a,5,6,7,8,8a-hexa- and cis-(+/-)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting materials, were resolved in a classical way by the formation of diastereomeric salts, and each was converted to optically active phthalazinone in an enantioselective manner. The absolute configuration of the (+)-enantiomer of cis-hexahydrophthalazinone (+)-12 was determined by X-ray crystallography. The carbon atoms at the 4a and 8a positions were found to have the S- and R-configuration, respectively. In the present series of hexa- and tetrahydrophthalazinones, stereoselectivity for PDE4 inhibition is observed; the cis-(+)-enantiomers of the phthalazinones display high inhibitory activity, whereas their (-)-counterparts exhibit only weak to moderate activity. It is likely that all cis-(+)-phthalazinones have a (4aS,8aR)-configuration and vice versa for the cis-(-)-analogues. In the current series, the N-adamantan-2-yl analogue (+)-14 shows the most potent inhibition of PDE4 (pIC(50) = 9.3); the corresponding (-)-enantiomer is 250-fold less active. In addition, the N-substituted tetrahydrophthalazinones under study were investigated for their in vivo antiinflammatory activities by examining the suppression of arachidonic acid (AA) induced mouse ear edema formation. In this assay analogues (+)-14 and (+)-15 were found to be potent antiinflammatory agents showing about 50% inhibition at 30 micromol/kg po.
|
Inhibitory concentration against phosphodiesterase 4 (PDE4) in cytosol of human neutrophils
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones.
Year : 2002
Volume : 45
Issue : 12
First Page : 2520
Last Page : 2525
Authors : Van der Mey M, Boss H, Hatzelmann A, Van der Laan IJ, Sterk GJ, Timmerman H.
Abstract : The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFalpha release and show moderate potency against fMLP-stimulated production of ROS.
|
Concentration for inhibitory activity against phosphodiesterase 4 from rat liver
|
None
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
Inhibition of phosphodiesterase 4 from rat liver at 0.1 uM
|
Rattus norvegicus
|
45.8
uM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
In vitro inhibitory activity against phosphodiesterase 4 from rat liver at concentration of 0.3 uM
|
None
|
54.0
uM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
In vitro inhibitory activity against phosphodiesterase 4 from rat liver at concentration of 1 uM
|
None
|
69.1
uM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
In vitro inhibitory activity against phosphodiesterase 4 from rat liver at concentration of 3 uM
|
None
|
72.2
uM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
Stimulation of acid secretion from rabbit parietal glands
|
Oryctolagus cuniculus
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
Year : 1998
Volume : 41
Issue : 6
First Page : 821
Last Page : 835
Authors : Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ.
Abstract : Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
|
Percent inhibition of T-lymphocyte activation in BALF from actively sensitized Brown norway rats at 2 mg/kg
|
Rattus norvegicus
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Binding affinity to rolipram binding site in isolated rat brain by rolipram binding assay
|
Rattus norvegicus
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors.
Year : 2001
Volume : 11
Issue : 5
First Page : 611
Last Page : 614
Authors : Nam G, Yoon CM, Kim E, Rhee CK, Kim JH, Shin JH, Kim SH.
Abstract : The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).
|
Percent inhibition of neutrophil activation in BALF from actively sensitized Brown norway rats at 2 mg/kg
|
Rattus norvegicus
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
EPO activity for activation of eosinophil cells in BALF from actively sensitized Brown norway rats
|
Rattus norvegicus
|
41.0
%
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Percent inhibition of eosinophil activation in BALF from actively sensitized Brown norway rats at 2 mg/kg
|
Rattus norvegicus
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 675
Last Page : 682
Authors : Hersperger R, Bray-French K, Mazzoni L, Müller T.
Abstract : Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
|
Inhibition of [3H]rolipram binding to Wistar rat brain membranes
|
Rattus norvegicus
|
49.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors.
Year : 2000
Volume : 43
Issue : 25
First Page : 4850
Last Page : 4867
Authors : Burnouf C, Auclair E, Avenel N, Bertin B, Bigot C, Calvet A, Chan K, Durand C, Fasquelle V, Féru F, Gilbertsen R, Jacobelli H, Kebsi A, Lallier E, Maignel J, Martin B, Milano S, Ouagued M, Pascal Y, Pruniaux MP, Puaud J, Rocher MN, Terrasse C, Wrigglesworth R, Doherty AM.
Abstract : The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
|
Inhibition of TNF-alpha synthesis in human monocytes
|
Homo sapiens
|
158.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.
Year : 2001
Volume : 11
Issue : 1
First Page : 33
Last Page : 37
Authors : Napoletano M, Norcini G, Pellacini F, Marchini F, Morazzoni G, Ferlenga P, Pradella L.
Abstract : This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.
|
Inhibition of lipopolysaccharide (LPS)-induced TNF alpha release by human monocytes
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
Year : 1998
Volume : 41
Issue : 6
First Page : 821
Last Page : 835
Authors : Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ.
Abstract : Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.
|
Inhibitory activity against recombinant phosphodiesterase 4B (PDE4B) of human mononuclear lymphocytes
|
None
|
71.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors.
Year : 2002
Volume : 12
Issue : 4
First Page : 653
Last Page : 658
Authors : Andrés JI, Alonso JM, Díaz A, Fernández J, Iturrino L, Martínez P, Matesanz E, Freyne EJ, Deroose F, Boeckx G, Petit D, Diels G, Megens A, Somers M, Van Wauwe J, Stoppie P, Cools M, De Clerck F, Peeters D, de Chaffoy D.
Abstract : This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
|
Inhibition of human phosphodiesterase 4
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3449
Last Page : 3462
Authors : Manallack DT, Hughes RA, Thompson PE.
|
Inhibition of human eosinophil phosphodiesterase
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.
Year : 2007
Volume : 50
Issue : 2
First Page : 344
Last Page : 349
Authors : Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW.
Abstract : The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
|
Inhibition of human recombinant PDE4B
|
Homo sapiens
|
84.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.
Year : 2007
Volume : 50
Issue : 2
First Page : 344
Last Page : 349
Authors : Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW.
Abstract : The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
|
Inhibition of human recombinant PDE4A
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.
Year : 2007
Volume : 50
Issue : 2
First Page : 344
Last Page : 349
Authors : Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW.
Abstract : The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
|
Inhibition of human recombinant PDE4C
|
Homo sapiens
|
610.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.
Year : 2007
Volume : 50
Issue : 2
First Page : 344
Last Page : 349
Authors : Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW.
Abstract : The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
|
Inhibition of human recombinant PDE4D
|
Homo sapiens
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.
Year : 2007
Volume : 50
Issue : 2
First Page : 344
Last Page : 349
Authors : Duplantier AJ, Bachert EL, Cheng JB, Cohan VL, Jenkinson TH, Kraus KG, McKechney MW, Pillar JD, Watson JW.
Abstract : The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.
|
Inhibition of human PDE4 at 0.075 uM after 20 mins
|
Homo sapiens
|
45.28
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted-2-(4-phenylethynyl-phenyl)-1H-benzimidazoles and N-substituted 2[4-(4,4-dimethyl-thiochroman-6-yl-ethynyl)-phenyl)-1H-benzimidazoles.
Year : 2008
Volume : 43
Issue : 5
First Page : 986
Last Page : 995
Authors : Vinodkumar R, Vaidya SD, Siva Kumar BV, Bhise UN, Bhirud SB, Mashelkar UC.
Abstract : Synthesis of a series of novel and functionalized benzimidazole derivatives by the condensation of OPDA with 4-bromobenzoic acid and subsequent reactions of the product obtained with phenylacetylene and 6-ethynyl-4,4-dimethylthiochroman utilising Sonogashira coupling has been reported. The Sonogashira coupling products were then alkylated at the benzimidazole -NH with different electrophilic reagents leading to functionalized derivatives. All the compounds synthesized were screened for their potential anti-bacterial, anti-asthmatic and anti-diabetic properties, which exhibited moderate activities in screening studies in vitro.
|
Inhibition of PDE4
|
None
|
65.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease.
Year : 2008
Volume : 51
Issue : 18
First Page : 5471
Last Page : 5489
Authors : Kodimuthali A, Jabaris SS, Pal M.
|
Inhibition of TNFalpha release in human whole blood
|
Homo sapiens
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease.
Year : 2008
Volume : 51
Issue : 18
First Page : 5471
Last Page : 5489
Authors : Kodimuthali A, Jabaris SS, Pal M.
|
Inhibition of human PDE4D
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Year : 2010
Volume : 18
Issue : 6
First Page : 2204
Last Page : 2218
Authors : Ehrman TM, Barlow DJ, Hylands PJ.
Abstract : Chinese herbs were screened for compounds which may be active against four targets involved in inflammation, using pharmacophore-assisted docking. Multiple LigandScout (LS) pharmacophores built from ligand-receptor complexes in the protein databank (PDB) were first employed to select compounds. These compounds were then docked using LS-derived templates and ranked according to docking score. The targets comprised cyclo-oxygenases 1 & 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK) and type 4 cAMP-specific phosphodiesterase (PDE4). The results revealed that multi-target inhibitors are likely to be relatively common in Chinese herbs. Details of their distribution are given, in addition to experimental evidence supporting these results. Examples of compounds predicted to be active against at least three targets are presented, and their features outlined. The distribution of herbs containing predicted inhibitors was also analysed in relation to 192 Chinese formulas from over 50 herbal categories. Among those found to contain a high proportion of these herbs were formulas traditionally used to treat fever, headache, rheumatoid arthritis, inflammatory bowel disorders, skin disease, cancer, and traumatic injury. Relationships between multi-target drug discovery and Chinese medicine are discussed.
|
Inhibition of human PDE4B
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Year : 2010
Volume : 18
Issue : 6
First Page : 2204
Last Page : 2218
Authors : Ehrman TM, Barlow DJ, Hylands PJ.
Abstract : Chinese herbs were screened for compounds which may be active against four targets involved in inflammation, using pharmacophore-assisted docking. Multiple LigandScout (LS) pharmacophores built from ligand-receptor complexes in the protein databank (PDB) were first employed to select compounds. These compounds were then docked using LS-derived templates and ranked according to docking score. The targets comprised cyclo-oxygenases 1 & 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK) and type 4 cAMP-specific phosphodiesterase (PDE4). The results revealed that multi-target inhibitors are likely to be relatively common in Chinese herbs. Details of their distribution are given, in addition to experimental evidence supporting these results. Examples of compounds predicted to be active against at least three targets are presented, and their features outlined. The distribution of herbs containing predicted inhibitors was also analysed in relation to 192 Chinese formulas from over 50 herbal categories. Among those found to contain a high proportion of these herbs were formulas traditionally used to treat fever, headache, rheumatoid arthritis, inflammatory bowel disorders, skin disease, cancer, and traumatic injury. Relationships between multi-target drug discovery and Chinese medicine are discussed.
|
Inhibition of human PDE4B1 incubated for 10 mins using cAMP and [3H]cAMP substrates
|
Homo sapiens
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of selective PDE4B inhibitors.
Year : 2009
Volume : 19
Issue : 12
First Page : 3174
Last Page : 3176
Authors : Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T, Nagumo H, Kodama T, Takemura M, Ohtsuka Y, Nakamura J, Tsujita R, Kawasaki K, Yokoi H, Kawanishi M.
Abstract : In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.
|
Inhibition of human PDE4D3 incubated for 10 mins using cAMP and [3H]cAMP substrates
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of selective PDE4B inhibitors.
Year : 2009
Volume : 19
Issue : 12
First Page : 3174
Last Page : 3176
Authors : Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T, Nagumo H, Kodama T, Takemura M, Ohtsuka Y, Nakamura J, Tsujita R, Kawasaki K, Yokoi H, Kawanishi M.
Abstract : In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.
|
Inhibition of neutropenia in ferret assessed as inhibition of LPS-induced change in number of neutrophils in lung lavage at 10 mg/kg, po
|
Mustela putorius furo
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of selective PDE4B inhibitors.
Year : 2009
Volume : 19
Issue : 12
First Page : 3174
Last Page : 3176
Authors : Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T, Nagumo H, Kodama T, Takemura M, Ohtsuka Y, Nakamura J, Tsujita R, Kawasaki K, Yokoi H, Kawanishi M.
Abstract : In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.
|
Inhibition of PDE4
|
None
|
95.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 4
First Page : 1523
Last Page : 1526
Authors : Shan WJ, Huang L, Zhou Q, Jiang HL, Luo ZH, Lai KF, Li XS.
Abstract : We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 μM, which was more potent than phthalazinone, IC(50)=0.520 μM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).
|
Inhibition of human recombinant PDE4B2-mediated cAMP hydrolysis for 30 mins by colorimetric assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 4
First Page : 1523
Last Page : 1526
Authors : Shan WJ, Huang L, Zhou Q, Jiang HL, Luo ZH, Lai KF, Li XS.
Abstract : We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 μM, which was more potent than phthalazinone, IC(50)=0.520 μM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).
|
Antiinflammatory activity in A/J mouse assessed as inhibition of LPS-induced airway elastance provoked by methacholine at 3 mg/kg, po administered 1 hr prior to LPS-challenge measured after 18 hrs relative to vehicle-treated control
|
Mus musculus
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.
Year : 2012
Volume : 55
Issue : 17
First Page : 7525
Last Page : 7545
Authors : Kümmerle AE, Schmitt M, Cardozo SV, Lugnier C, Villa P, Lopes AB, Romeiro NC, Justiniano H, Martins MA, Fraga CA, Bourguignon JJ, Barreiro EJ.
Abstract : Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
|
Antiinflammatory activity in A/J mouse assessed as inhibition of LPS-induced airway resistance provoked by methacholine at 3 mg/kg, po administered 1 hr prior to LPS-challenge measured after 18 hrs relative to vehicle-treated control
|
Mus musculus
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.
Year : 2012
Volume : 55
Issue : 17
First Page : 7525
Last Page : 7545
Authors : Kümmerle AE, Schmitt M, Cardozo SV, Lugnier C, Villa P, Lopes AB, Romeiro NC, Justiniano H, Martins MA, Fraga CA, Bourguignon JJ, Barreiro EJ.
Abstract : Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
|
Antiinflammatory activity in A/J mouse assessed as inhibition of neutrophil accumulation in bronchoalveolar space at 3 mg/kg, po administered 1 hr prior to LPS-challenge measured after 18 hrs relative to vehicle-treated control
|
Mus musculus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.
Year : 2012
Volume : 55
Issue : 17
First Page : 7525
Last Page : 7545
Authors : Kümmerle AE, Schmitt M, Cardozo SV, Lugnier C, Villa P, Lopes AB, Romeiro NC, Justiniano H, Martins MA, Fraga CA, Bourguignon JJ, Barreiro EJ.
Abstract : Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
|
Inhibition of LPS-induced neutrophilia in ferret COPD model BAL-fluid at 10 mg/kg, po
|
Mustela putorius furo
|
35.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of triazines as potent, selective and orally active PDE4 inhibitors.
Year : 2013
Volume : 23
Issue : 15
First Page : 4308
Last Page : 4314
Authors : Gewald R, Grunwald C, Egerland U.
Abstract : Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor.
|
Inhibition of human full length PDE4A4 expressed in baculovirus infected sf21 cells
|
Homo sapiens
|
62.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of triazines as potent, selective and orally active PDE4 inhibitors.
Year : 2013
Volume : 23
Issue : 15
First Page : 4308
Last Page : 4314
Authors : Gewald R, Grunwald C, Egerland U.
Abstract : Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor.
|
Inhibition of PDE4B2 (unknown origin)
|
Homo sapiens
|
95.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors.
Year : 2014
Volume : 24
Issue : 1
First Page : 249
Last Page : 253
Authors : Huang L, Shan W, Zhou Q, Xie J, Lai K, Li X.
Abstract : A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092μM).
|
Inhibition of human recombinant PDE4B2 assessed as inhibition of cAMP hydrolysis by colorimetric assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors.
Year : 2014
Volume : 24
Issue : 1
First Page : 249
Last Page : 253
Authors : Huang L, Shan W, Zhou Q, Xie J, Lai K, Li X.
Abstract : A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092μM).
|
Inhibition of PDE4 (unknown origin)
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-one derivatives as a new series of Phosphodiesterase 4 (PDE4) inhibitors.
Year : 2017
Volume : 27
Issue : 1
First Page : 24
Last Page : 29
Authors : Guariento S, Karawajczyk A, Bull JA, Marchini G, Bielska M, Iwanowa X, Bruno O, Fossa P, Giordanetto F.
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.
|
Inhibition of PDE4D (unknown origin) using cAMP as substrate
|
Homo sapiens
|
120.0
nM
|
|
Journal : J Med Chem
Title : Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
Year : 2019
Volume : 62
Issue : 11
First Page : 5579
Last Page : 5593
Authors : Zhang X, Dong G, Li H, Chen W, Li J, Feng C, Gu Z, Zhu F, Zhang R, Li M, Tang W, Liu H, Xu Y.
Abstract : Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
|
Inhibition of human PDE4D catalytic domain using [3H]-cAMP or [3H]-cGMP incubated for 30 mins by scintillation counting method
|
Homo sapiens
|
11.0
nM
|
|
Title : FMO3 inhibitors for treating pain
|
Inhibition of human His-tagged PDE4B catalytic domain expressed in Escherichia coli BL21-CodonPlus(DE3) cells using [3H]cAMP or [3H]cGMP as substrate incubated for 30 mins by scintillation counting method
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
Inhibition of human His-tagged PDE4D catalytic domain expressed in Escherichia coli BL21-CodonPlus(DE3) cells using [3H]cAMP or [3H]cGMP as substrate incubated for 30 mins by scintillation counting method
|
Homo sapiens
|
11.0
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.37
%
|
|
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
|
0.06
%
|
|
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
|
0.06
%
|
|
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.
|
Antiinflammatory activity against A/J mouse assessed as decrease in LPS-induced airway hyperreactivity at 3 umol/kg, po treated via gavage for 1 hr before LPS stimulation measured after 24 hrs by whole body plethysmography relative to control
|
Mus musculus
|
94.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Antiinflammatory activity against A/J mouse assessed as decrease in LPS-induced TNFalpha production in lungs at 3 umol/kg, po treated via gavage for 1 hr before LPS stimulation and measured after 24 hrs by ELISA relative to control
|
Mus musculus
|
98.9
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4A1A using FAM-cAMP as substrate measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4C using FAM-cAMP as substrate at 10 uM measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
98.5
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4D3 using FAM-cAMP as substrate measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4A1A using FAM-cAMP as substrate at 10 uM measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
91.3
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4B1 using FAM-cAMP as substrate at 10 uM measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
91.3
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of human recombinant PDE4D3 using FAM-cAMP as substrate at 10 uM measured after 1 hr by IMAP TR-FRET assay
|
Homo sapiens
|
98.8
%
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of PDE4A (unknown origin)
|
Homo sapiens
|
160.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of PDE4B (unknown origin)
|
Homo sapiens
|
120.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of PDE4D (unknown origin)
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Year : 2020
Volume : 204
First Page : 112492
Last Page : 112492
Authors : Nunes IKDC,de Souza ET,Martins IRR,Barbosa G,Moraes Junior MO,Medeiros MM,Silva SWD,Balliano TL,da Silva BA,Silva PMR,Carvalho VF,Martins MA,Lima LM
Abstract : Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
|
Inhibition of PDE4 (unknown origin)
|
Homo sapiens
|
95.0
nM
|
|
Journal : J Med Chem
Title : Advances in the Development of Phosphodiesterase-4 Inhibitors.
Year : 2020
Volume : 63
Issue : 19
First Page : 10594
Last Page : 10617
Authors : Peng T,Qi B,He J,Ke H,Shi J
Abstract : Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.
