Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
J Pharmacol Exp Ther ; 352(3): 559-67, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25576075

RESUMO

This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE)4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7- and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC50 = 0.026 ± 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., >40) and displayed >20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC50 values) the release of tumor necrosis factor-α from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-γ from CD4(+) T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED50 = 0.205 µmol/kg) and leukocyte infiltration (ED50 = 0.188 µmol/kg) with an efficacy comparable to a high dose of budesonide (1 µmol/kg i.p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/metabolismo , Administração por Inalação , Administração Tópica , Animais , Furões , Masculino , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley
2.
J Med Chem ; 66(8): 5622-5656, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37017110

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.


Assuntos
Fibrose Pulmonar Idiopática , Receptores de Ácidos Lisofosfatídicos , Humanos , Lisofosfolipídeos
3.
J Med Chem ; 66(16): 11476-11497, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37561958

RESUMO

Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92a is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10f was identified as a chemically stable, potent, and in vivo balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.


Assuntos
Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Anti-Inflamatórios/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
4.
J Med Chem ; 64(13): 9100-9119, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142835

RESUMO

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Cobaias , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Receptor Muscarínico M3/metabolismo , Relação Estrutura-Atividade
5.
J Med Chem ; 50(7): 1571-83, 2007 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-17352462

RESUMO

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.


Assuntos
Imidazolidinas/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Administração Oral , Animais , Função Atrial/efeitos dos fármacos , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Feminino , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M2/antagonistas & inibidores , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia
6.
J Med Chem ; 50(7): 1693-7, 2007 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-17352463

RESUMO

Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.


Assuntos
Broncodilatadores/química , Imidazolidinas/síntese química , Compostos de Amônio Quaternário/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/síntese química , Broncodilatadores/farmacologia , Células CHO , Cricetinae , Cricetulus , Cobaias , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Contração Miocárdica/efeitos dos fármacos , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
7.
J Med Chem ; 60(24): 10026-10046, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29200281

RESUMO

Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.


Assuntos
Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Relação Estrutura-Atividade , Administração por Inalação , Animais , Sítios de Ligação , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Humanos , Masculino , Inibidores da Fosfodiesterase 4/administração & dosagem , Eosinofilia Pulmonar/tratamento farmacológico , Pirrolidinas/química , Ratos Endogâmicos BN , Doenças Respiratórias/tratamento farmacológico , Tiazóis/química
8.
J Med Chem ; 49(17): 5051-8, 2006 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-16913695

RESUMO

Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Alcaloides/química , Carbamatos/química , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Sítios de Ligação/efeitos dos fármacos , Encéfalo/enzimologia , Carbamatos/administração & dosagem , Carbamatos/farmacologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Cristalização , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Torpedo
9.
Eur J Pharmacol ; 752: 84-91, 2015 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-25701725

RESUMO

Several investigations have demonstrated a mild clinical status in patients with ß-globin disorders and congenital high persistence of foetal haemoglobin. This can be mimicked by a pharmacological increase of foetal γ-globin genes expression and foetal haemoglobin production. Our goal was to apply a multistep assay including few screening methods (benzidine staining, RT-PCR and HPLC analyses) and erythroid cellular model systems (the K562 cell line and erythroid precursors collected from peripheral blood) to select erythroid differentiation agents with foetal haemoglobin inducing potential. With this methodology, we have identified a butyric acid derivative, namely the 4174 cyclopropanecarboxylic acid compound, able to induce erythroid differentiation without antiproliferative effect in K562 cells and increase of γ-globin gene expression in erythroid precursor cells. The results are relevant for pharmacological treatments of haemoglobinopathies, including ß-thalassaemia and sickle cell anaemia.


Assuntos
Ácido Butírico/química , Ácido Butírico/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Eritroides/citologia , Células Eritroides/efeitos dos fármacos , Hemoglobina Fetal/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Patentes como Assunto , Talassemia beta/genética , Talassemia beta/patologia , gama-Globinas/genética
10.
J Med Chem ; 57(3): 793-816, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24400806

RESUMO

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Asma/tratamento farmacológico , Benzoatos/síntese química , Pneumopatias Obstrutivas/tratamento farmacológico , Inibidores da Fosfodiesterase 4/síntese química , Sulfonamidas/síntese química , para-Aminobenzoatos/síntese química , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Linhagem Celular , Doença Crônica , Cristalografia por Raios X , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Eosinofilia/patologia , Ésteres , Cobaias , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Simulação de Acoplamento Molecular , Ovalbumina , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Conformação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , para-Aminobenzoatos/química , para-Aminobenzoatos/farmacologia
11.
Eur J Med Chem ; 44(2): 745-54, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18571290

RESUMO

A series of carbamides derived from 1,2:5,6-di-O-isopropylidene-D-gluco- and D-allofuranose as well as their 5,6-O-deprotected analogues (2 and 4) and methyl 3,4-O-isopropylidene-alpha- and beta-D-galactopyranosides (5 and 6) have been prepared in order to evaluate their ability to induce erythroid differentiation of human erythroleukemic K562 cells. Twenty out of 51 carbamides tested exhibit an appreciable activity as inducers of erythroid differentiation and have been fully characterized and described.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Leucemia Eritroblástica Aguda/patologia , Monossacarídeos/síntese química , Monossacarídeos/farmacologia , Ureia/análogos & derivados , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Eritroides/efeitos dos fármacos , Galactose , Glucose , Humanos , Células K562 , Leucemia Eritroblástica Aguda/tratamento farmacológico , Pentoses , Relação Estrutura-Atividade
12.
J Pharmacol Exp Ther ; 303(1): 196-203, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12235251

RESUMO

We have identified a new benzopyran derivative, 3-(4-methoxy) phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-2H-1-benzopyran-7-ol hydrochloride (CHF 4227), with improved in vivo estrogen agonist/antagonist effects. CHF 4227 binds with high affinity to the human estrogen receptor-alpha and -beta (dissociation constant K(i) = 0.017 and 0.099 nM, respectively). In immature rats, oral administration of CHF 4227 for 3 days inhibited the uterotrophic action of 17alpha-ethynyl estradiol (EE2) (ED(50) = 0.016 mg/kg. day); raloxifene was 25 times less potent as estrogen antagonist (ED(50) = 0.39 mg/kg. day), whereas both compounds were found to be devoid of uterotrophic activity. In line with its estrogen antagonist effect, CHF 4227 significantly prevented the development of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors, the incidence being reduced from 87.5 to 26.3% 6 months after DMBA administration. In ovariectomized (OVX) rats treated orally for 4 weeks, CHF 4227 completely inhibited OVX effects on bone density (ED(50) = 0.003 mg/kg. day) and on serum osteocalcin levels. The protective effects on bone were comparable with those achieved with EE2, whereas raloxifene was less efficacious and 100 times less potent. CHF 4227 reduced serum cholesterol (ED(50) = 0.007 mg/kg. day) and had little to no stimulatory effects on uterine weight, uterine peroxidase activity, and endometrium epithelial thickness. In conclusion, CHF 4227 compares favorably in efficacy and potency with raloxifene in preventing bone loss and in antagonizing EE2 stimulation of the uterus. This profile along with the minimal uterine stimulation suggests a therapeutic advantage to CHF 4227 over EE2 or raloxifene for the treatment of postmenopausal women.


Assuntos
Anticarcinógenos/farmacologia , Benzopiranos/farmacologia , Densidade Óssea/efeitos dos fármacos , Estrogênios/farmacologia , Neoplasias Mamárias Experimentais/prevenção & controle , Piperidinas/farmacologia , Receptores de Estrogênio/fisiologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Anticarcinógenos/química , Benzopiranos/química , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Estrogênios/química , Feminino , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Estrutura Molecular , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Piperidinas/química , Cloridrato de Raloxifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/efeitos dos fármacos , Útero/anatomia & histologia , Útero/efeitos dos fármacos
13.
J Pharmacol Exp Ther ; 300(3): 802-9, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11861784

RESUMO

We have discovered a new, nonsteroidal, estrogen agonist/antagonist, 3-phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl] methyl]-2H-1-benzopyran-7-ol (CHF 4056). The aim of this study was to determine the effects of CHF 4056 on a series of parameters (body weight, uteri, serum cholesterol, and bones) that were previously shown to be sensitive to estrogens and to selective estrogen receptor modulators (SERMs). CHF 4056 is a benzopyran derivative that binds with high affinity to the human estrogen receptors alpha and beta (dissociation constant K(i) of 0.041 and 0.157 nM, respectively). In immature rats, CHF 4056 induced a full estrogen antagonism (half-maximal efficacious dose = 0.33 mg/kg x day p.o.) coupled with a lack of uterine stimulatory activity, whereas the structurally related SERM levormeloxifene demonstrated a maximal partial agonist effect of approximately 65% that of 17alpha-ethynyl estradiol (EE2). In ovariectomized (OVX) rats, CHF 4056 (0.1-1 mg/kg x day p.o. for 4 weeks) significantly reduced OVX-induced bone loss in the lumbar spine L1-4 and OVX-induced increase in serum osteocalcin. These protective effects on bone tissue were comparable with those of 0.1 mg/kg x day EE2. In the same experimental conditions, serum cholesterol was significantly lower in the CHF 4056-treated animals, compared with vehicle-treated OVX rats. In line with the results observed in immature rats, also in OVX rats CHF 4056 diverged dramatically from EE2 and levormeloxifene in its lack of significant estrogenic effects on uterine tissue. In conclusion, CHF 4056 is a new SERM that produces beneficial effects on bone and cholesterol levels, while maintaining antagonist effects on the uterus.


Assuntos
Benzopiranos/farmacologia , Piperidinas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Útero/efeitos dos fármacos , Animais , Densidade Óssea/efeitos dos fármacos , Colesterol/sangue , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Peroxidase de Eosinófilo , Congêneres do Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Etinilestradiol/farmacologia , Feminino , Humanos , Técnicas In Vitro , Ovariectomia , Peroxidases/metabolismo , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Útero/crescimento & desenvolvimento , Útero/metabolismo
14.
Bioorg Med Chem ; 12(14): 3763-82, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15210143

RESUMO

The synthesis, binding affinity for estrogen receptor subtypes (ER alpha and ER beta) and pharmacological activity on rat uterus of a new class of potent ligands, characterized by a 3-phenylbenzopyran scaffold with a basic side chain in position 4, are reported. Some of these compounds, endowed with very high receptor affinity, showed potent inhibition of agonist-stimulated uterine growth, with no or limited proliferative effect. Binding affinity mostly depended on the nature and position of substituents at the 3-phenyl ring, while the uterine activity seems to be affected by basic chain length. Compound 9c (CHF4227) showed excellent binding affinity and antagonist activity on the uterus. The docking of benzopyran derivatives explained the structure-affinity relationships observed for 3-phenyl substitution: a small, hydrophobic 4'-substituent could interact with a small accessory binding cavity, while di-substitution at 4' and 3' led to some ER alpha selectivity. This selectivity can be ascribed to differences in amino acid composition and side chain conformation in the region accommodating the 3-phenyl ring at human ER alpha and ER beta ligand-binding domain.


Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Benzopiranos/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Ratos , Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA