Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314

RESUMO

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

2.
J Med Chem ; 59(19): 8848-8858, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27564419

RESUMO

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Cães , Halogenação , Humanos , Macaca fascicularis , Masculino , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade
3.
J Med Chem ; 57(18): 7509-22, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25165888

RESUMO

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).


Assuntos
Fármacos Antiobesidade/farmacologia , Descoberta de Drogas , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Masculino , Ratos
4.
Bioorg Med Chem Lett ; 21(14): 4141-5, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21696952

RESUMO

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.


Assuntos
Amidas/química , Araquidonato 15-Lipoxigenase/química , Inibidores de Lipoxigenase/química , Pirazóis/química , Amidas/síntese química , Amidas/farmacologia , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
5.
Bioorg Med Chem Lett ; 20(3): 1128-33, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20022752

RESUMO

Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.


Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Quinazolinonas/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Humanos , Masculino , Obesidade/metabolismo , Ligação Proteica/fisiologia , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/metabolismo
6.
J Med Chem ; 51(9): 2722-33, 2008 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-18412317

RESUMO

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.


Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Pirimidinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colesterol/biossíntese , Colesterol/sangue , Cristalografia por Raios X , Cães , Feminino , Cobaias , Haplorrinos , Humanos , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Moleculares , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/toxicidade
7.
Bioorg Med Chem Lett ; 17(18): 5115-20, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17656086

RESUMO

A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.


Assuntos
Imidazóis/farmacologia , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Imidazóis/química , Inibidores de Lipoxigenase/química , Masculino , Ratos , Ratos Sprague-Dawley
8.
Bioorg Med Chem Lett ; 15(5): 1435-40, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713402

RESUMO

A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores de Lipoxigenase , Sulfonamidas/farmacologia , Triptaminas/química , Animais , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
9.
Bioorg Med Chem Lett ; 14(1): 177-80, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684323

RESUMO

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Guanidinas/administração & dosagem , Imidazóis/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Guanidinas/química , Guanidinas/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Proteínas de Membrana/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Estereoisomerismo
10.
J Org Chem ; 62(21): 7088-7089, 1997 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-11671806
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...