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1.
Clin Gastroenterol Hepatol ; 19(8): 1602-1610.e1, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31927106

RESUMO

BACKGROUND & AIMS: There is consensus on the criteria used to define acute severe ulcerative colitis (ASUC) and on patient management, but it has been a challenge to identify patients at risk for colectomy based on data collected at hospital admission. We aimed to develop a system to determine patients' risk of colectomy within 1 y of hospital admission for ASUC based on clinical, biomarker, and endoscopy data. METHODS: We performed a retrospective analysis of consecutive patients with ASUC treated with corticosteroids, ciclosporin, or tumor necrosis factor (TNF) antagonists and admitted to 2 hospitals in France from 2002 through 2017. Patients were followed until colectomy or loss of follow up. A total of 270 patients with ASUC were included in the final analysis, with a median follow-up time of 30 months (derivation cohort). Independent risk factors identified by Cox multivariate analysis were used to develop a system to identify patients at risk for colectomy 1 y after ASUC. We developed a scoring system based on these 4 factors (1 point for each item) to identify high-risk (score 3 or 4) vs low-risk (score 0) patients. We validated this system using data from an independent cohort of 185 patients with ASUC treated from 2006 through 2017 at 2 centers in France. RESULTS: In the derivation cohort, the cumulative risk of colectomy was 12.3% (95% CI, 8.6-16.8). Based on multivariate analysis, previous treatment with TNF antagonists or thiopurines (hazard ratio [HR], 3.86; 95% CI, 1.82-8.18), Clostridioides difficile infection (HR, 3.73; 95% CI, 1.11-12.55), serum level of C-reactive protein above 30 mg/L (HR, 3.06; 95% CI, 1.11-8.43), and serum level of albumin below 30 g/L (HR, 2.67; 95% CI, 1.20-5.92) were associated with increased risk of colectomy. In the derivation cohort, the cumulative risks of colectomy within 1 y in patients with scores of 0, 1, 2, 3, or 4 were 0.0%, 9.4% (95% CI, 4.3%-16.7%), 10.6% (95% CI, 5.6%-17.4%), 51.2% (95% CI, 26.6%-71.3%), and 100%. Negative predictive values ranged from 87% (95% CI, 82%-91%) to 92% (95% CI, 88%-95.0%). Findings from the validation cohort were consistent with findings from the derivation cohort. CONCLUSIONS: We developed a scoring system to identify patients at low-risk vs high-risk for colectomy within 1 y of hospitalization for ASUC, based on previous treatment with TNF antagonists or thiopurines, C difficile infection, and serum levels of CRP and albumin. The system was validated in an external cohort.


Assuntos
Colite Ulcerativa , Colectomia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Hospitalização , Hospitais , Humanos , Estudos Retrospectivos , Índice de Gravidade de Doença
2.
Pharmaceuticals (Basel) ; 13(8)2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784450

RESUMO

A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (-)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (-)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30298122

RESUMO

Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.


Assuntos
Doença de Crohn/complicações , Doença de Crohn/microbiologia , Íleo/microbiologia , Yersiniose/epidemiologia , Yersiniose/microbiologia , Yersinia/isolamento & purificação , DNA Girase/genética , Humanos , Reação em Cadeia da Polimerase , Prevalência , Yersinia/classificação , Yersinia/genética
4.
Aliment Pharmacol Ther ; 48(8): 831-838, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30194687

RESUMO

BACKGROUND: Genital fistulas represent a devastating complication of Crohn's disease. Only studies with small sample sizes have evaluated the efficacy of anti-TNF therapy for this complication. AIMS: To assess the efficacy of anti-TNF therapy for genital fistulas complicating Crohn's disease and to identify predictive factors associated with clinical response at 1 year. METHODS: Consecutive patients treated with anti-TNF therapy for genital fistulas complicating Crohn's disease from 1999 to 2016 in 19 French centres from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif were included in a retrospective cohort study. Outcome was clinical fistula closure at 1 year. RESULTS: Among the 204 women with genital fistulas who received anti-TNF therapy, 131 were analysed. The first anti-TNF given was infliximab (79%), adalimumab (20%), or certolizumab (1%). At start of anti-TNF therapy, 56% of patients had seton drainage and 53% had concomitant immunosuppressive treatment. A complementary surgery was performed during the first year in 10 patients (8%). At 1 year, 37% of patients had complete clinical fistula closure, 22% had a partial response, and 41% had no response. Among patients without complementary surgery, 34% (41/121) had complete clinical fistula closure. Only complementary surgery was associated with better response on multivariate analysis (adjusted relative risk: 2.02, 95% CI: 1.25-3.26, P = 0.0043). CONCLUSIONS: In the anti-TNF era, approximately one-third of patients with genital fistula in Crohn's disease had complete fistula closure at 1 year. Collaboration between surgeons and gastroenterologists appears to be very important to improve the rate of fistula closure.


Assuntos
Doença de Crohn/complicações , Fístula/tratamento farmacológico , Imunossupressores/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adulto , Certolizumab Pegol/uso terapêutico , Drenagem , Feminino , Fístula/etiologia , Humanos , Imunoterapia , Infliximab/uso terapêutico , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
5.
J Gastrointest Oncol ; 9(3): E15-E18, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29998025

RESUMO

Oxaliplatin given systemically is associated with pneumonitis in less than 1% of cases. This case report describes acute respiratory failure, due to bronchiolitis organising pneumonia, in a patient with colorectal carcinoma being treated with hyperthermic intraperitoneal chemotherapy which included oxaliplatin and CPT-11 (irinotecan). The clinical course, the lack of an identifiable infectious agent and the complete response to corticosteroids suggested a drug-induced cause. After ruling out CPT-11, oxaliplatin was considered to be the causal agent. The unusual feature of this case was that pneumonitis developed after intraperitoneal administration of oxaliplatin. Oxaliplatin-associated respiratory complications can occur whatever route the drug is administered.

6.
Bioorg Med Chem ; 17(18): 6715-27, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19682911

RESUMO

The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC(50)=39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Indóis/química , Indóis/farmacologia , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Animais , Antineoplásicos/síntese química , Carcinoma/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Indóis/síntese química , Leucemia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Neoplasias do Colo do Útero/tratamento farmacológico
8.
J Enzyme Inhib Med Chem ; 23(5): 686-95, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18821257

RESUMO

New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Antineoplásicos/síntese química , Indóis/química , Indóis/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Glicina , Humanos , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 23(5): 728-38, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18821260

RESUMO

In this study, the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs has been described. Pharmacomodulation was carried out at N(1) and C(5) of the indole ring and at the level of the propanamide chain. N(3)-pyridinylmethyl-[1(4-chlorobenzyl-5-chloroindol-3-yl)propanamide represents one of the most potent compounds in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.


Assuntos
Amidas/síntese química , Indóis/síntese química , Inflamação/tratamento farmacológico , Amidas/farmacologia , Animais , Dexametasona , Ibuprofeno , Indóis/farmacologia , Inflamação/prevenção & controle , Camundongos , Relação Estrutura-Atividade
10.
J Enzyme Inhib Med Chem ; 22(5): 667-76, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18035835

RESUMO

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC50 values ranging between 0.054 and 0.050 microM. In the other sub-series, eight 3-(alpha-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC50 value of 0.052 microM. All target compounds were further evaluated against 17alpha-hydroxylase/C17,20-lyase to determine their selectivity profile.


Assuntos
Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Azóis/química , Indóis/síntese química , Indóis/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Inibidores da Aromatase/química , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Indóis/química , Concentração Inibidora 50 , Masculino , Microssomos/química , Microssomos/efeitos dos fármacos , Estrutura Molecular , Placenta/enzimologia , Ratos , Relação Estrutura-Atividade , Testículo/enzimologia
11.
Bioorg Med Chem Lett ; 17(13): 3686-9, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17482460

RESUMO

A series of fluconazole analogues 5-20 incorporating azaindole and indole moieties were prepared using oxirane intermediates synthesized under microwave irradiation. All of the compounds were evaluated in vitro against two clinically important fungi, Candida albicans and Aspergillus fumigatus. Four derivatives 6, 13, 14 and 18 exerted high antifungal activity against C. albicans with MIC(80) values 3- to 28-fold lower than that of fluconazole.


Assuntos
Antifúngicos/química , Antifúngicos/síntese química , Química Farmacêutica/métodos , Fluconazol/química , Fluconazol/síntese química , Testes de Sensibilidade Microbiana , Aspergillus fumigatus/metabolismo , Candida albicans/metabolismo , Desenho de Fármacos , Farmacorresistência Fúngica , Humanos , Concentração Inibidora 50 , Modelos Químicos , Fatores de Tempo , Triazóis/química
12.
J Enzyme Inhib Med Chem ; 21(3): 277-83, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16918075

RESUMO

Two 3-(alpha-azolylbenzyl)indoles were evaluated against Leishmania amastigotes. Both compounds proved to be very active against intracellular and axenic amastigotes. The IC50 values of the imidazole derivative, PM17, and the triazole analogue, PM19, against L. mexicana axenic amastigotes, were 4.4 +/- 0.1 and 6.4 +/- 0.1 microM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 microM and PM19 had an IC50 of 1.3 microM. In a Balb/c mice model of L. major leishmaniasis, administration of PM17 led to a clear-cut parasite burden reduction: 98.9% in the spleen, 79.0% in the liver and 49.9% in the popliteal node draining the cutaneous lesion. As anticipated, it was brought to the fore that PM17 decreases ergosterol biosynthesis leading to membrane fungal cell alterations. Moreover it was proved that this imidazole antifungal agent induces a parasite burden-correlated decrease in interleukine-4 production both in the splenocyte and the popliteal node of the mouse.


Assuntos
Antiprotozoários/farmacologia , Azóis/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Leishmania major/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Triazóis/farmacologia , Animais , Antiprotozoários/síntese química , Azóis/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ergosterol/biossíntese , Imidazóis/administração & dosagem , Indóis/administração & dosagem , Indóis/síntese química , Interleucina-4/biossíntese , Leishmania major/crescimento & desenvolvimento , Leishmania mexicana/crescimento & desenvolvimento , Leishmaniose/parasitologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fosfolipases A/antagonistas & inibidores , Sensibilidade e Especificidade , Baço/efeitos dos fármacos , Baço/parasitologia , Triazóis/administração & dosagem
13.
Bioorg Med Chem Lett ; 16(5): 1134-7, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16380254

RESUMO

The synthesis and the aromatase (CYP19) inhibitory activity of 5-[(aryl)(imidazol-1-yl)methyl]-1H-indoles were reported. Among the tested racemate compounds, 5-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-indole 8b emerged as a potent CYP19 inhibitor (IC(50)=15.3 nM). Chiral chromatography allowed isolation of the (+) enantiomer 8b2, which was about twice as active as the racemate (IC(50)=9 nM).


Assuntos
Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Imidazóis/química , Indóis/química , Indóis/farmacologia , Inibidores da Aromatase/química , Indóis/síntese química , Concentração Inibidora 50 , Metilação , Estrutura Molecular , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por Substrato
14.
J Enzyme Inhib Med Chem ; 20(6): 581-5, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16408794

RESUMO

A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.


Assuntos
Aromatase/química , Estrenos/química , Fadrozol/química , Modelos Moleculares , Sequência de Aminoácidos , Animais , Aromatase/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Fadrozol/farmacologia , Humanos , Ligação de Hidrogênio , Dados de Sequência Molecular , Estrutura Molecular , Coelhos , Alinhamento de Sequência , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 14(21): 5441-4, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15454241

RESUMO

The authors have described the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs. Pharmacomodulation was carried out at N-1 and C-5 of the indole ring and at the level of the propanamide chain. N-(pyridin-3-ylmethyl)-3-[5-chloro-1-(4-chlorobenzyl)-indol-3-yl]propanamide 32 represents one of the most potent compounds evaluated in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.


Assuntos
Amidas/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Indóis/síntese química , Propano/análogos & derivados , Propano/síntese química , Piridinas/síntese química , Administração Cutânea , Administração Oral , Amidas/química , Amidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Orelha Externa , Edema/induzido quimicamente , Edema/tratamento farmacológico , Indóis/química , Indóis/farmacologia , Camundongos , Alcamidas Poli-Insaturadas , Propano/química , Propano/farmacologia , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol
16.
J Enzyme Inhib Med Chem ; 19(6): 451-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15662948

RESUMO

The present study was designed to investigate conazoles as new antileishmanial agents. Several 3-imidazolylalkyl-indoles were prepared under mild reaction conditions and pharmacomodulation at N1 and C5 of the indole ring and at the level of the alkyl chain (R) was carried out starting from the corresponding 3-formylindoles 7-10. All target imidazolyl compounds 38-52 were evaluated in vitro against Leishmania mexicana promastigotes; ketoconazole, amphotericin B and meglumine antimoniate were used as references. Eight out of fifteen compounds (40,43,44,47,48, 50, 51 and 52) exerted similar activity to ketoconazole, with IC50 values in the range of 2.10-3.30 microg/mL. However the most potent compound, 1-(2-bromobenzyl)-3-(1H-imidazol-1-ylmethyl)-1H-indole (38), exhibited IC50 value (0.011+/-0.003 microg/mL) 270-fold lower than that of ketoconazole. Four compounds (38, 43, 50 and 52) were also tested against intracellular amastigotes of L. mexicana; compound 38 exhibited the highest activity with an IC50 value of 0.018+/-0.004 microg/mL.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Indóis/síntese química , Indóis/farmacologia , Leishmania mexicana/efeitos dos fármacos , Anfotericina B/farmacologia , Animais , Antiprotozoários/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Indóis/química , Cetoconazol/farmacologia , Macrófagos Peritoneais/parasitologia , Meglumina/farmacologia , Antimoniato de Meglumina , Estrutura Molecular , Compostos Organometálicos/farmacologia , Testes de Sensibilidade Parasitária , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Enzyme Inhib Med Chem ; 19(6): 549-57, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15662958

RESUMO

The present study was designed to follow our pharmacomodulation work in the field of non-steroidal aromatase inhibitors. All target compounds 12a-h and 28a-h were tested in vitro for human placental aromatase inhibition, using testosterone or androstenedione as the substrate for the aromatase enzyme and the IC50 and relative potency to aminoglutethimide data are included. A SAR study indicated that 3-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-1-ethyl-2-methyl-1H-indole (28 g) was a highly potent and selective aromatase inhibitor with IC50 value of 0.025 microM. 28 g was also a weak inhibitor of androstenedione synthesis.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/efeitos dos fármacos , Indóis/farmacologia , Androstenodiona/química , Aromatase/química , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Testosterona/química
18.
J Enzyme Inhib Med Chem ; 18(3): 253-7, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14506916

RESUMO

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)-2,3-dihydrobenzo[b]furan-2-ones 8-10 and 3-(3,5-dimethylpyrrol-2-ylmethylene)-2,3-dihydrobenzo[b]furan-2-one 11, analogues of SU-5416, as potential inhibitors of angiogenesis, are reported. Compounds 8 and 11 were prepared by a Knoevenagel reaction starting from 2-hydroxyphenylacetic acid 2 and 4-formylimidazole 5 or 2-formyl-3,5-dimethylpyrrole 7, followed by acid-catalysed cyclodehydration. For compounds 9 and 10, an alternative method was used; it consisted in carrying out the Knoevenagel reaction with the 2,3-dihydrobenzo[b]furan-2-ones 3 and 4. The antiangiogenic activity of these compounds was evaluated in the three-dimensional in vitro rat aortic rings test at 1microM. At this concentration, compound 11 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density index at 1 microM of 11 and SU-5416 were 30 +/- 10 and 22 +/- 4% of control, respectively.


Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Indóis/síntese química , Indóis/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Inibidores da Angiogênese/química , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/citologia , Indóis/química , Espectroscopia de Ressonância Magnética , Masculino , Modelos Químicos , Pirróis/química , Ratos , Ratos Endogâmicos F344 , Temperatura
19.
J Enzyme Inhib Med Chem ; 18(3): 243-52, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14506915

RESUMO

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration.


Assuntos
Inibidores da Angiogênese/farmacologia , Indóis/síntese química , Indóis/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Indóis/química , Masculino , Metilação , Modelos Químicos , Nitrogênio/química , Proteínas Tirosina Quinases/metabolismo , Pirróis/química , Ratos , Ratos Endogâmicos F344
20.
J Enzyme Inhib Med Chem ; 18(2): 155-8, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12943199

RESUMO

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition).


Assuntos
Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Tretinoína/metabolismo , Triazóis/farmacologia , Animais , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Hidroxilação , Técnicas In Vitro , Indóis/química , Cetoconazol/farmacologia , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triazóis/química
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