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1.
Neuropharmacology ; 101: 358-69, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26471422

RESUMO

The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity/anticonvulsant effects). Calculated TIs for A-1295120, CMPPE, rac-BHFF, GS39783, and A-1474713 were 5.31x, 5.00x, 4.74x, 3.41x, and 1.83x, respectively, whereas baclofen was <1. The results presented here suggest the DBA/2J mouse AGS test is a potentially useful screening model for detecting PD effects of GABA(B) PAMs and can provide an initial read-out on target-related motor side-effects. Furthermore, an improved TI was observed for PAMs compared to baclofen, indicating the PAM approach may be a viable therapeutic alternative to baclofen.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Baclofeno/uso terapêutico , Convulsões/tratamento farmacológico , Estimulação Acústica/efeitos adversos , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ciclopentanos/farmacologia , Interações Medicamentosas , Agonistas GABAérgicos/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos DBA , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Convulsões/etiologia , Isótopos de Enxofre/farmacocinética
2.
J Med Chem ; 58(23): 9154-70, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26509640

RESUMO

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.


Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Ácido Azetidinocarboxílico/administração & dosagem , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Ácido Azetidinocarboxílico/farmacologia , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Linhagem Celular , Envelhecimento Cognitivo , Cães , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo
3.
Med J Aust ; 200(9): 541-5, 2014 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-24835719

RESUMO

OBJECTIVE: To evaluate the processes by which pharmaceuticals are added to the formularies of Australian paediatric hospitals. DESIGN: Descriptive study of the processes and outcomes of all submissions to Australian paediatric hospital drug and therapeutics committees from 1 July 2010 to 31 December 2011. SETTING: All eight tertiary paediatric hospitals in Australia. PARTICIPANTS: Interviews with committee secretaries or delegates and document analysis. MAIN OUTCOME MEASURES: Total number of formulary applications, stratified by therapeutic class, approval rates for each hospital and quality of supporting information. RESULTS: One hundred and twenty applications were considered during the study period, with most applications approved (range, 67%-100%). Neurological agents were the most common therapeutic class considered. A conflict of interest was declared for 10 applications (8%). Forty-five (38%) were independently reviewed by a statewide medicines advisory committee or hospital pharmacist. Several committees approved identical applications during the period of review and with different outcomes. For applications submitted for new drugs or new indications (95 applications), supporting data included randomised controlled trials (37/95), case series (36/95), product information (34/95) and narrative reviews (29/95). Few applications (14/95) included a systematic review or meta-analysis. No application included an evaluation of the risk of bias of supporting studies. CONCLUSIONS: There is limited high-quality evidence informing paediatric hospital-based drug approvals. Approval processes vary considerably among institutions with substantial duplication of effort and variable outcomes. Resources and training appear insufficient given the technical complexity of submissions. A national, standardised approach to hospital-based drug evaluation could reduce overlap and improve decision making.


Assuntos
Formulários de Hospitais como Assunto/normas , Hospitais Pediátricos , Austrália
4.
J Org Chem ; 74(5): 1932-8, 2009 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-19175330

RESUMO

A straightforward approach to novel (5-nitropyridin-2-yl)alkyl and (5-nitropyridin-3-yl)alkyl carbamate building blocks is presented in this study. Their construction is achieved by condensation of N-carbamate alpha- and beta-amino carbonyl derivatives with 1-methyl-3,5-dinitro-2-pyridone 1 under microwave irradiation. Judiciously chosen modifications in the nature of the parent carbonyl starting material has influenced the regiochemical outcome of the reaction and allowed an efficient access to novel nitrogen-containing scaffolds. Compounds sharing morphological similarities have been gathered in three libraries differing from each other in a single structural parameter.


Assuntos
Carbamatos/síntese química , Micro-Ondas , Piridinas/química , Carbamatos/química , Ciclização , Estrutura Molecular , Estereoisomerismo
5.
J Med Chem ; 50(15): 3651-60, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17583335

RESUMO

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.


Assuntos
Analgésicos/síntese química , Indazóis/síntese química , Compostos de Fenilureia/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cães , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Microssomos Hepáticos/metabolismo , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Ratos , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética , Ureia/farmacologia
6.
Bioorg Med Chem Lett ; 17(14): 3894-9, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17507218

RESUMO

SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.


Assuntos
Analgésicos/farmacologia , Inflamação/tratamento farmacológico , Modelos Biológicos , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/farmacologia , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Metilação , Ratos , Ureia/farmacocinética , Ureia/uso terapêutico
7.
Bioorg Med Chem ; 14(14): 4740-9, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16621571

RESUMO

Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.


Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Técnicas In Vitro , Cinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Medição da Dor , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo , Ureia/síntese química , Ureia/química , Ureia/farmacologia
8.
Br J Pharmacol ; 143(1): 81-90, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15302680

RESUMO

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels. 2. A-151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide-sensitive whole-cell current and fluorescence-based membrane potential responses (-log EC(50)=7.63) in guinea-pig bladder smooth muscle cells. 3. Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4-dihydropyridine opener [(125)I]A-312110. A-151892 displaced [(125)I]A-312110 binding to bladder membranes with a -log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites. 4. In pig bladder strips, A-151892 suppressed phasic, carbachol-evoked and electrical field stimulus-evoked contractility in a glibenclamide-reversible manner with -log IC(50) values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (-log IC(50)=7.81) and portal vein (-log IC(50)=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle. 5. In vivo, A-151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED(35%) values of 8.05 and 7.43, respectively. 6. These results demonstrate that naphthylamide analogs exemplified by A-151892 are novel K(ATP) channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms.


Assuntos
Acetamidas/farmacologia , Trifosfato de Adenosina/fisiologia , Naftalenos/farmacologia , Canais de Potássio/agonistas , Animais , Barbitúricos/metabolismo , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Feminino , Guanidinas/farmacologia , Cobaias , Técnicas In Vitro , Radioisótopos do Iodo , Isoxazóis/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Patch-Clamp , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/efeitos dos fármacos
9.
J Med Chem ; 47(12): 3163-79, 2004 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15163196

RESUMO

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.


Assuntos
Trifosfato de Adenosina/fisiologia , Óxidos S-Cíclicos/síntese química , Canais de Potássio/efeitos dos fármacos , Quinolonas/síntese química , Bexiga Urinária/efeitos dos fármacos , Animais , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Estimulação Elétrica , Cobaias , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Potenciais da Membrana , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Quinolonas/química , Quinolonas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Urodinâmica/efeitos dos fármacos
10.
J Med Chem ; 47(12): 3180-92, 2004 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15163197

RESUMO

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.


Assuntos
Trifosfato de Adenosina/fisiologia , Di-Hidropiridinas/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Canais de Potássio/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Estimulação Elétrica , Cobaias , Hemodinâmica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Ligação de Hidrogênio , Técnicas In Vitro , Potenciais da Membrana , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Urodinâmica/efeitos dos fármacos
11.
Bioorg Med Chem Lett ; 13(12): 2003-7, 2003 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-12781183

RESUMO

2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent.


Assuntos
Aminas/síntese química , Aminas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Aminas/química , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Cálcio/metabolismo , Linhagem Celular , Humanos , Técnicas In Vitro , Indóis/química , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Canais de Potássio Cálcio-Ativados/metabolismo , Relação Estrutura-Atividade , Suínos , Transfecção , Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/tratamento farmacológico , Transtornos Urinários/tratamento farmacológico
12.
Bioorg Med Chem Lett ; 13(13): 2131-5, 2003 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-12798320

RESUMO

The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H(3) receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H(3) receptor were discovered.


Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Ratos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Proteínas Recombinantes/química , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 13(10): 1741-4, 2003 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-12729655

RESUMO

We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips. Additionally, A-151892 was found to selectively inhibit unstable bladder contractions in vivo in an obstructed rat model of myogenic bladder function


Assuntos
Amidas/síntese química , Amidas/farmacologia , Canais de Potássio/agonistas , Transportadores de Cassetes de Ligação de ATP/agonistas , Transportadores de Cassetes de Ligação de ATP/genética , Amidas/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Corantes Fluorescentes , Humanos , Hipertrofia/tratamento farmacológico , Masculino , Potenciais da Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Naftalenos/administração & dosagem , Naftalenos/síntese química , Naftalenos/farmacologia , Canais de Potássio/genética , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Canais de Potássio Corretores do Fluxo de Internalização/genética , Ratos , Ratos Sprague-Dawley , Receptores de Droga/agonistas , Receptores de Droga/genética , Relação Estrutura-Atividade , Receptores de Sulfonilureias , Suínos , Transfecção , Bexiga Urinária/patologia
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