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1.
Eur J Med Chem ; 89: 597-605, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25462268

RESUMO

1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11ß-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Naftóis/farmacologia , Sulfóxidos/farmacologia , Animais , Citocromo P-450 CYP11B2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Modelos Moleculares , Naftóis/síntese química , Naftóis/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfóxidos/síntese química , Sulfóxidos/química
2.
J Med Chem ; 54(7): 2307-19, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21384875

RESUMO

Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11ß-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Citocromo P-450 CYP11B2/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Especificidade por Substrato
3.
J Comput Aided Mol Des ; 25(1): 51-66, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21088982

RESUMO

A series of 51 5-HT(2A) partial agonistic arylethylamines (primary or benzylamines) from different structural classes (indoles, methoxybenzenes, quinazolinediones) was investigated by fragment regression analysis (FRA), docking and 3D-QSAR approaches. The data, pEC(50) values and intrinsic activities (E(max)) on rat arteries, show high variability of pEC(50) from 4 to 10 and of E(max) from 15 to 70%. FRA indicates which substructures affect potency or intrinsic activity. The high contribution of halogens in para position of phenethylamines to pEC(50) points to a specific hydrophobic pocket. Other results suggest the significance of hydrogen bonds of the aryl moiety for activation and the contrary effect of benzyl groups on affinity (increasing) and intrinsic activity (decreasing). Results from fragment regression and data on all available mutants were considered to derive a common binding site at the rat 5-HT(2A) receptor. After generation and MD simulations of a receptor model based on the ß(2)-adrenoceptor structure, typical derivatives were docked, leading to the suggestion of common interactions, e.g., with serines in TM3 and TM5 and with a cluster of aromatic amino acids in TM5 and TM6. The whole series was aligned by docking and minimization of the complexes. The pEC(50) values correlate well with Sybyl docking energies and hydrophobicity of the aryl moieties. With this alignment, CoMFA and CoMSIA approaches based on a training set of 36 and a test set of 15 compounds were performed. The correlation of pEC(50) with steric, electrostatic, hydrophobic and H-bond acceptor fields resulted in sufficient fit (q (2): 0.75-0.8, r (2): 0.92-0.95) and predictive power (r (pred) (2) : 0.85-0.88). The important interaction regions largely reflect the patterns provided by the putative binding site. In particular, the fit of the aryl moieties and benzyl substituents to two hydrophobic pockets is evident.


Assuntos
Etilaminas/química , Etilaminas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Modelos Biológicos , Modelos Moleculares , Modelos Estatísticos , Dados de Sequência Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Ratos
4.
J Steroid Biochem Mol Biol ; 116(3-5): 121-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19427380

RESUMO

Aldosterone plays a crucial role in salt and water homeostasis but in case of pathologically increased plasma aldosterone levels it is also involved in the development and the progression of severe cardiovascular diseases like heart failure and myocardial fibrosis. For the treatment of these diseases we propose inhibition of the aldosterone forming enzyme CYP11B2 as a new pharmacological strategy. We recently developed in vitro highly potent and selective inhibitors of human CYP11B2, but the evidence of their in vivo activity is still missing. For this purpose, rat aldosterone synthase gene was cloned and expressed in V79MZ cells to establish a new screening assay for the identification of "rat-active" substances. Compound 7 from the class of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones showed a moderate inhibitory effect (65% at 2 microM) on rat CYP11B2 in vitro. Furthermore, it diminished the conversion of deoxycorticosterone to aldosterone in rat adrenals and significantly reduced plasma aldosterone levels in vivo.


Assuntos
Aldosterona/biossíntese , Citocromo P-450 CYP11B2/antagonistas & inibidores , Quinolonas/farmacologia , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Aldosterona/sangue , Animais , Linhagem Celular , Cricetinae , Cricetulus , Citocromo P-450 CYP11B2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Quinolonas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
5.
J Med Chem ; 51(24): 8077-87, 2008 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19049427

RESUMO

Pyridine substituted naphthalenes (e.g., I-III) constitute a class of potent inhibitors of aldosterone synthase (CYP11B2). To overcome the unwanted inhibition of the hepatic enzyme CYP1A2, we aimed at reducing the number of aromatic carbons of these molecules because aromaticity has previously been identified to correlate positively with CYP1A2 inhibition. As hypothesized, inhibitors with a tetrahydronaphthalene type molecular scaffold (1-11) exhibit a decreased CYP1A2 inhibition. However, tetralone 9 turned out to be cytotoxic to the human cell line U-937 at higher concentrations. Consequent structural optimization culminated in the discovery of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones (12-26), with 12, a bioisostere of 9, being nontoxic up to 200 microM. The investigated molecules are highly selective toward both CYP1A2 and a wide range of other cytochrome P450 enzymes and show a good pharmacokinetic profile in vivo (e.g., 12 with a peroral bioavailability of 71%). Furthermore, isoquinoline derivative 21 proved to significantly reduce plasma aldosterone levels of ACTH stimulated rats.


Assuntos
Química Farmacêutica/métodos , Citocromo P-450 CYP11B2/antagonistas & inibidores , Citocromo P-450 CYP1A2/química , Inibidores Enzimáticos/síntese química , Piridinas/química , Quinolonas/química , Animais , Carbono/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Fígado/enzimologia , Ratos , Temperatura , Células U937
6.
J Med Chem ; 51(19): 6138-49, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18763754

RESUMO

Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.


Assuntos
Ácidos Carbocíclicos/química , Citocromo P-450 CYP11B2/antagonistas & inibidores , Desenho de Fármacos , Naftalenos/síntese química , Naftalenos/farmacologia , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Estereoisomerismo , Relação Estrutura-Atividade
7.
J Med Chem ; 51(16): 5064-74, 2008 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-18672861

RESUMO

Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 microM concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores do Citocromo P-450 CYP1A2 , Naftalenos/síntese química , Animais , Citocromo P-450 CYP1A2 , Fibrose/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Miocárdio/patologia , Naftalenos/farmacocinética , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade
8.
Org Lett ; 7(7): 1327-9, 2005 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-15787498

RESUMO

[reaction: see text] The tricyclic core of vibsanin E was constructed without the use of a protecting group in six steps. The El Gaïed Baylis-Hillman variant was key to allowing the Brønsted acid induced tandem cyclization forming rings B and C in one operation.


Assuntos
Diterpenos/química , Diterpenos/síntese química , Ciclização , Estrutura Molecular , Viburnum/química
9.
Org Biomol Chem ; 2(6): 806-7, 2004 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-15007404

RESUMO

Certain 3-azabicyclo[3.3.1]nonane derivatives undergo unprecedented stereospecific skeletal cleavage when subjected to light affording a novel heterotricyclic skeleton.


Assuntos
Alcanos/química , Compostos Aza/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/química , Estrutura Molecular , Fotoquímica , Estereoisomerismo
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