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1.
Eur J Pharmacol ; 815: 219-232, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28899697

RESUMO

Degradation of podocyte structural integrity and function are hallmarks of proteinuric chronic kidney disease. In vivo, injury of podocytes manifests itself in the form of disruption of foot process morphology and associated cytoskeletal architecture, de-differentiation, and loss of adhesion to the glomerular basement membrane. Given the critical role played by this highly specialized cell type in maintaining glomerular filtration, there is a need for improved physiologically relevant cellular models that enable detection of disease-relevant indicators of podocyte perturbation. We have addressed this need by evaluating a subclone of conditionally immortalized human podocytes through quantitative benchmarking against freshly isolated primary human podocytes. Benchmarking was performed by measuring key phenotypic parameters, expression of podocyte specific proteins and multiparametric responses to stressors that model different aspects of podocyte perturbation. We subsequently employed the subcloned cells to profile the protective activity of structurally distinct adenosine kinase inhibitors. Our results support the translatability of our cellular model and set the stage for broader screening of renoprotective compounds with a view to eventually treat proteinuric kidney disease.


Assuntos
Citoproteção/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Insuficiência Renal Crônica/patologia , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fenótipo
2.
J Med Chem ; 51(6): 1904-12, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18311894

RESUMO

A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Cetonas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ligação Competitiva , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Ligantes , Conformação Molecular , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
3.
J Med Chem ; 49(25): 7450-65, 2006 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-17149874

RESUMO

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.


Assuntos
Benzamidas/síntese química , Óxidos N-Cíclicos/síntese química , Disfunção Erétil/tratamento farmacológico , Receptores de Dopamina D4/agonistas , Potenciais de Ação , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/fisiologia , Haplorrinos , Humanos , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/fisiologia , Ratos , Relação Estrutura-Atividade
4.
J Pharmacol Sci ; 102(2): 231-8, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17050951

RESUMO

Soluble guanylyl cyclase (sGC) is a target enzyme for endogenous nitric oxide (NO), and it converts GTP to cyclic GMP (guanosine 3',5'-cyclic monophosphate) as part of a cascade that results in physiological processes such as smooth muscle relaxation, neurotransmission, and inhibition of platelet aggregation. Here we examine a representative of the novel class sCG activators, A-778935 ((+/-)-cis-3-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-yl]-N-(3-hydroxy-cyclohexyl)-acrylamide). A-778935 activated sGC synergistically with sodium nitroprusside (SNP) over a wide range of concentration, inducing up to 420-fold activation. A specific inhibitor of sGC, ODQ (1H-[1,2,4]-oxadiazolo[4,3-alpha]quinoxalin-1-one), did not block basal sGC activity, but competitively inhibited the activation by A-778935. A-778935, with or without SNP, did not activate heme-deficient sGC, indicating that the activation of sGC by A-778935 is fully heme-dependent. A-778935 increased intracellular cGMP level dose-dependently in smooth muscle cells. In the presence of 1 microM SNP, a lower concentration of A-778935 increased cGMP than A-778935 alone, and the cGMP concentration reached the same level at 100 microM of A-778935. A-778935 relaxed cavernosum tissue strips in a dose-dependent manner; and in the presence of 1 microM SNP, A-778935 relaxed the strips more potently, shifting the dose-response curve to the left. This novel activator of sGC may have potential efficacy for the treatment of a variety of disorders associated with reduced NO signaling.


Assuntos
Acrilamidas/farmacologia , Ativadores de Enzimas/farmacologia , Guanilato Ciclase/metabolismo , Óxido Nítrico/fisiologia , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Acrilamidas/síntese química , Acrilamidas/química , Animais , Baculoviridae/genética , Linhagem Celular , Clonagem Molecular , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Técnicas In Vitro , Masculino , Estrutura Molecular , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/metabolismo , Piridinas/síntese química , Piridinas/química , Coelhos , Ratos , Guanilil Ciclase Solúvel
5.
J Med Chem ; 49(17): 5093-109, 2006 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-16913699

RESUMO

A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.


Assuntos
Disfunção Erétil/tratamento farmacológico , Oximas/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D4/agonistas , Animais , Benzamidas/química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Furões , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Oximas/síntese química , Oximas/química , Piperazinas/síntese química , Piperazinas/química , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade
6.
Pharmacol Biochem Behav ; 81(1): 211-9, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15894081

RESUMO

Agents that activate the dopamine D2-like family of receptors elicit emesis in humans and other species with a vomiting/emetic reflex; however, the lack of dopamine receptor subtype selective agonists has hampered an understanding of which dopamine D2-like receptor subtype(s) contributes to the emetic response. In this study, stable cell lines expressing the ferret dopamine D2-long (D2L) and D4 receptors were used to characterize known dopamine agonists via radioligand binding and calcium ion flux assays, while emetic activity of these dopamine receptor agonists was determined in male ferrets. Latencies to first emetic event, average number of emetic episodes, and stereotypical behaviors which may be indicative of nausea were also determined. Agonists at dopamine D1-like and D4 receptors had no emetic effect in ferrets. Conversely, stimulation of dopamine D2 and/or D3 receptors resulted in a robust emetic response characterized by a relatively short latency (<15 min) and multiple emetic events. Competitive antagonists of dopamine D2-like receptors (domperidone, haloperidol) dose-dependently blocked the emetic response to PNU95666E, a dopamine D2 receptor selective agonist. Thus, dopamine D2 and/or D3 receptor agonists elicit emesis, while dopamine D1/D5 or D4 receptor-selective agonists are devoid of emetic properties.


Assuntos
Agonistas de Dopamina/toxicidade , Furões/metabolismo , Receptores de Dopamina D2/agonistas , Vômito/induzido quimicamente , Animais , Linhagem Celular , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Humanos , Masculino , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Dopamina D2/metabolismo , Vômito/metabolismo
7.
Bioorg Med Chem ; 13(15): 4667-78, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15896964

RESUMO

A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.


Assuntos
Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de Dopamina D2/agonistas , Linhagem Celular , Agonistas de Dopamina/química , Humanos , Ligantes , Estrutura Molecular , Piperidinas/síntese química , Receptores de Dopamina D4 , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 14(20): 5095-8, 2004 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-15380206

RESUMO

The first selective dopamine D4 agonist radioligand is described. The synthesis of these piperazine radioligands relied on the transformation of brominated precursors 4a and 4b with tritium gas in the presence of a sensitive cyano functional group. The specific activity of these two radioligands was measured and [3H]6b found to be suitable for use in D4 saturation and competition binding studies. The synthesis, biological, and radioactivity of this new agonist radioligand as well as preliminary SAR will be discussed.


Assuntos
Acetamidas/síntese química , Piperazinas/síntese química , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Linhagem Celular , Humanos , Técnicas In Vitro , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Receptores de Dopamina D4 , Relação Estrutura-Atividade , Trítio
9.
Biochem Pharmacol ; 68(4): 761-72, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15276084

RESUMO

The goal of this study was to develop a new approach to study the pharmacology of the dopamine D(4) receptor that could be used in comparative studies with dopamine D(2) and D(3) receptors. Stable HEK-293 cell lines co-expressing recombinant human D(2L), D(3) or D(4) receptors along with Galpha(qo5) cDNA were prepared. Dopamine induced a robust, transient calcium signal in these cell lines with EC(50)s for D(2L), D(3) and D(4) of 18.0, 11.9 and 2.2 nM, respectively. Reported D(4)-selective agonists CP226269 and PD168077 were potent, partial D(4) agonists exhibiting 31-1700-fold selectivity for D(4) over D(3) or D(2). Non-selective D(2)-like agonists apomorphine and quinpirole showed full efficacy but did not discriminate across the three receptors. D(3)-selective agonists 7-hydroxy-DPAT and PD128907 were potent but non-selective D(2)-like agonists. The reported D(3) partial agonist BP-897 exhibited minimal agonist activity at D(3) but was a potent D(3) antagonist and a partial D(4) agonist. Other D(2)-like antagonists, haloperidol, clozapine, and domperidone showed concentration-dependent inhibition of dopamine responses at all three receptors with K(i) ranging from 0.05 to 48.3 nM. The D(3) selective antagonist S33084 and D(4)-selective antagonist L-745870 were highly selective for D(3) and D(4) receptors with K(b) of 0.7 and 0.1 nM, respectively. Stable co-expression of D(2)-like receptors with chimeric Galpha(qo5) proteins in HEK-293 cells is an efficient method to study receptor activation in a common cellular background and an efficient method for direct comparison of ligand affinity and efficacy across human D(2L), D(3) and D(4) receptors.


Assuntos
Cálcio/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Transporte Biológico , Células CHO , Linhagem Celular , Células Cultivadas , Cricetinae , Dopamina , Humanos , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Proteínas Recombinantes de Fusão/metabolismo
10.
J Med Chem ; 47(15): 3853-64, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15239663

RESUMO

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.


Assuntos
Benzimidazóis/síntese química , Disfunção Erétil/tratamento farmacológico , Piperazinas/síntese química , Piridinas/síntese química , Receptores de Dopamina D2/agonistas , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Linhagem Celular , Furões , Humanos , Masculino , Ereção Peniana/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/toxicidade , Piridinas/química , Piridinas/farmacologia , Piridinas/toxicidade , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Dopamina D4 , Relação Estrutura-Atividade , Vômito/induzido quimicamente
11.
Bioorg Med Chem ; 12(13): 3471-83, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15186832

RESUMO

Diaryl piperazine acetamides were identified as potent and selective dopamine D(4) receptor agonists. Our strategy is based on an amide bond reversal of an acid sensitive, dopamine D(4) receptor partial agonist, PD 168077. This reversal provided compounds with excellent potency and improved stability. Systematic evaluation of the substitution on the aryl piperazine portion revealed a significant effect on functional activity. The synthesis and biological activity of these new dopamine D(4) agonists is discussed.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Acetamidas/síntese química , Cálcio/metabolismo , Linhagem Celular , Agonistas de Dopamina/química , Humanos , Estrutura Molecular , Ensaio Radioligante , Receptores de Dopamina D4
12.
J Med Chem ; 47(9): 2348-55, 2004 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-15084133

RESUMO

A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.


Assuntos
Benzimidazóis/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptores de Dopamina D2/agonistas , Benzimidazóis/química , Benzimidazóis/farmacologia , Ligação Competitiva , Linhagem Celular , Antagonistas dos Receptores de Dopamina D2 , Humanos , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Receptores de Dopamina D4 , Relação Estrutura-Atividade , Termodinâmica
13.
Life Sci ; 72(9): 1015-25, 2003 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-12495780

RESUMO

Nitric oxide (NO) is a key mediator in many physiological processes and one of the major receptors through which NO exerts its effects is soluble guanylyl cyclase. Guanylyl cyclase converts GTP to cyclic GMP as part of the cascade that results in physiological processes such as smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation and immune response. The properties of A-350619, a novel soluble guanylyl cyclase activator, were examined to determine the modulatory effect on the catalytic properties of soluble guanylyl cyclase. A-350619 increased V(max) from 0.1 to 14.5 micromol/min/mg (145 fold increase), and lowered K(m) from 300 to 50 microM (6 fold decrease). When YC-1 (another sGC activator) and A-350619 were combined, a 156 fold increase in V(max) and a 5 fold decrease in Km were observed, indicating that the modulation of the enzyme brought about by YC-1 and A-350619 are not additive, suggesting a common binding site. Activation of soluble guanylyl cyclase by A-350619 was partially inhibited by ODQ, a specific inhibitor of soluble guanylyl cyclase by oxidation of the enzyme heme. YC-1 and A-350619 after pre-treatment with N-omega-nitro-L-arginine, an NO-synthase inhibitor, relaxed cavernosum tissue strips in a dose-dependent manner with EC(50) of 50 microM and 80 microM, respectively. Addition of SNP potentiated the relaxation effect of YC-1 and A-350619, shifting the dose-response curve to the left to 3 microM and 10 microM, respectively. Consistent with its biochemical activity, A-350619 (1 micromol/kg) alone induced penile erection in a conscious rat model. Activation of soluble guanylyl cyclase in cavernosum tissue as an alternate method of enhancing the effect of NO may provide a novel treatment of sexual dysfunction.


Assuntos
Acrilamidas/farmacologia , Ativadores de Enzimas/farmacologia , Guanilato Ciclase/biossíntese , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Animais , Células Cultivadas , GMP Cíclico/biossíntese , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , Indazóis/farmacologia , Masculino , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso Vascular/enzimologia , Coelhos , Ratos , Ratos Wistar , Spodoptera/enzimologia
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