Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Bioorg Med Chem Lett ; 27(4): 1094-1098, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28089699

RESUMO

The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Piperazinas/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Humanos , Piperazinas/química , Piperazinas/uso terapêutico , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 19(6): 1830-4, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19237282

RESUMO

A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.


Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Administração Oral , Animais , Quimiotaxia , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Macaca mulatta , Modelos Químicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 18(4): 1374-7, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18215519

RESUMO

In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.


Assuntos
Ciclopentanos/química , Receptores CCR2/antagonistas & inibidores , Compostos de Espiro/química , Acetais/química , Acetais/farmacologia , Cristalografia por Raios X , Ciclopentanos/farmacologia , Humanos , Cinética , Conformação Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Receptores CCR2/metabolismo , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 18(3): 994-8, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18164199

RESUMO

This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.


Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Piperidinas/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Relação Estrutura-Atividade
7.
J Med Chem ; 60(9): 3594-3605, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28252959

RESUMO

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Líquida , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética
8.
J Med Chem ; 59(2): 609-23, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26709102

RESUMO

The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/toxicidade , Animais , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Feminino , Humanos , Lipidoses/induzido quimicamente , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Pirimidinonas/farmacocinética , Pirimidinonas/toxicidade , Pirrolidinas/farmacocinética , Pirrolidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Difração de Raios X
9.
J Med Chem ; 57(4): 1437-53, 2014 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-24437735

RESUMO

A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.


Assuntos
Acetanilidas/síntese química , Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/síntese química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular
10.
Diving Hyperb Med ; 42(3): 137-45, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22987460

RESUMO

INTRODUCTION: The Diver Emergency Service (DES) in Australia provides specialised medical advice on diving incidents 24 hours a day to divers, dive operators, families and health professionals. It is operated from the Hyperbaric Medicine Unit of the Royal Adelaide Hospital where the physician-on-call also carries the DES phone (1800-088200 or +61-8-8212-9242). METHODS: Data from calls to the service have been compiled into a computer database since 1991. Calls for the 17 years from 1991 through 2007 were analysed. RESULTS: A total of 6,083 calls were logged, an average of 358 calls a year. Calls from Queensland and New South Wales each accounted for 25% of calls. Calls originating from outside Australia have been increasing and now make up 25% of calls. The diver themselves initiated the call 50% of the time and 66% of the calls were about male divers. The age range of divers was 12 to 95 years old. The mean age has increased from 30 to 36 years, with a greater proportion of calls from divers aged 50 years or older (from 2% to 14%). The largest group of calls (37%) related to whether symptoms might be the result of decompression illness (DCI). DCI was considered to be the probable diagnosis in 17% of calls, and possible in a further 12%. Other common findings were barotrauma (11%) and questions regarding fitness to dive (15%). Older divers were more likely to call in relation to a medical problem. CONCLUSION: Interpretation of these data is qualitative but the prolonged collection period of 17 years allows some consideration of trends as to who calls the DES and why.


Assuntos
Doença da Descompressão/diagnóstico , Mergulho/estatística & dados numéricos , Serviços Médicos de Emergência/estatística & dados numéricos , Linhas Diretas/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Barotrauma/diagnóstico , Barotrauma/epidemiologia , Criança , Doença da Descompressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consulta Remota/estatística & dados numéricos , Distribuição por Sexo , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA