RESUMO
With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl-phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07±0.02 µM) in differentiated skeletal muscle cells in presence of insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.
Assuntos
Acetamidas/química , Ftalazinas/química , Tiazóis/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes , Insulina/farmacologia , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Ftalazinas/síntese química , Ftalazinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.
Assuntos
Doença de Chagas/tratamento farmacológico , Imidazóis/síntese química , Ftalazinas/síntese química , Pirazóis/síntese química , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Chlorocebus aethiops , Feminino , Histocitoquímica , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Microscopia Eletrônica de Transmissão , Ftalazinas/química , Ftalazinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Superóxido Dismutase/antagonistas & inibidores , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura , Células VeroRESUMO
Starting from phthalic anhydride, several new 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives were synthesized as potent anti-inflammatory agent. The study showed that the compounds 6h (6-(2-chlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine) and 6s (6-(4-aminophenoxy)-[1,2,4] triazolo[3,4-a]phthalazine-3-amine) exhibited the highest anti-inflammatory activity (81% and 83% inhibition, respectively, at 0.5 h after i.p. administration) which were slightly more potent than the reference drug Ibuprofen (61%). Furthermore, the peak activity of 6h and 6s was observed at the 3 h after p.o. administration, and they exhibited stronger anti-inflammatory activity than Ibuprofen at the dose of 50 mg/kg at the peak time.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ftalazinas/síntese química , Ftalazinas/farmacologia , Animais , Anti-Inflamatórios/química , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Ftalazinas/química , Espectrofotometria InfravermelhoRESUMO
New N-(dimethylamino)ethyl derivatives of phthalazinones and pyridopyridazinones 7, 9 were synthesized and assayed as potential analgesic agents in the hot-plate, tail-flick, and writhing tests. Pharmacological assay demonstrated that eight (in ten) of the newly synthesized compounds showed antinociceptive activity. Especially, 2-[2-(dimethylamino)ethyl]-4-phenyl-2H-phthalazin-1-one 7a showed remarkably higher antinociceptive activity in all tests. This is connected with influence on supraspinal, spinal, and peripheral structures. The decreased sensitivity to the pain stimulus in the hot-plate was higher than that of metamizole.
Assuntos
Analgésicos não Narcóticos/síntese química , Ftalazinas/síntese química , Piridazinas/síntese química , Analgésicos não Narcóticos/farmacologia , Animais , Dipirona , Avaliação Pré-Clínica de Medicamentos , Camundongos , Limiar da Dor/efeitos dos fármacos , Ftalazinas/farmacologia , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Ftalazinas/química , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Ftalazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ftalazinas/síntese química , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Ftalazinas/química , Poli(ADP-Ribose) Polimerase-1 , Ratos , Relação Estrutura-AtividadeRESUMO
In this study, 6-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 4-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesized by reacting 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone or 4-(4-aminophenyl)-1(2H)-phthalazinone compound with different 4-arylidene-2-phenyl-5(4H)-oxazolone derivatives. The vasodilator activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.
Assuntos
Ftalazinas/administração & dosagem , Ftalazinas/síntese química , Piridazinas/síntese química , Piridazinas/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial/instrumentação , Determinação da Pressão Arterial/métodos , Artérias Carótidas/citologia , Artérias Carótidas/efeitos dos fármacos , Clonidina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Ftalazinas/química , Cloreto de Potássio/antagonistas & inibidores , Cloreto de Potássio/farmacologia , Piridazinas/química , Ratos , Ovinos , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/químicaRESUMO
A solid-phase route for the preparation of 4a,5,8,8a-tetrahydrophthalazinon-1-ones employing the Diels-Alder reaction has been developed. Some of the new compounds have been tested for inhibition of LPS-stimulated TNF-alpha production in human whole blood from patients with chronic obstructive pulmonary disease (COPD). This evaluation revealed two compounds 17 and 18 of interest, incorporating an arylpiperazine moiety, which were found to inhibit LPS-induced TNF-alpha release like the well known anti-inflammatory PDE4 inhibitors, rolipram and roflumilast.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Ftalazinas/síntese química , Ftalazinas/farmacologia , Doença Pulmonar Obstrutiva Crônica/sangue , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Aminopiridinas/farmacologia , Anti-Inflamatórios não Esteroides/química , Benzamidas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Ciclopropanos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Inibidores de Fosfodiesterase/química , Ftalazinas/química , Rolipram/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Ftalazinas/síntese química , Sítios de Ligação , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Neutrófilos/enzimologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Ftalazinas/química , Ftalazinas/farmacologia , Rolipram/análogos & derivados , Relação Estrutura-AtividadeRESUMO
In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.
Assuntos
Anticonvulsivantes/síntese química , Ftalazinas/síntese química , Estimulação Acústica , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Células Cultivadas , Convulsivantes , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Agonistas de Aminoácidos Excitatórios , Isoxazóis , Ácido Caínico , Camundongos , Camundongos Endogâmicos DBA , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pentilenotetrazol , Ftalazinas/química , Ftalazinas/farmacologia , Propionatos , Receptores de AMPA/agonistas , Receptores de Ácido Caínico/agonistas , Convulsões/tratamento farmacológico , Convulsões/etiologia , Relação Estrutura-Atividade , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/síntese química , Inibidores Enzimáticos/síntese química , Ftalazinas/síntese química , Piridinas/síntese química , Animais , Antiasmáticos/química , Antiasmáticos/farmacologia , Antiasmáticos/toxicidade , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Furões , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Ftalazinas/química , Ftalazinas/farmacologia , Ftalazinas/toxicidade , Piridinas/química , Piridinas/farmacologia , Piridinas/toxicidade , Relação Estrutura-Atividade , Vômito/induzido quimicamenteAssuntos
Anti-Helmínticos/síntese química , Benzimidazóis/síntese química , Ftalazinas/síntese química , Animais , Anti-Helmínticos/uso terapêutico , Anti-Helmínticos/toxicidade , Benzimidazóis/uso terapêutico , Benzimidazóis/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Camundongos , Ftalazinas/uso terapêutico , Ftalazinas/toxicidade , Relação Estrutura-Atividade , Triquinelose/tratamento farmacológicoRESUMO
A series of phthalazine and 1,2,3-benzotriazine derivatives which have heterocyclylpiperidino groups was synthesized and tested for cardiotonic activity in anesthetized dogs. Several 6,7-dimethoxyphthalazine derivatives showed relatively potent cardiotonic activity comparable to that of amrinone.