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ACS Med Chem Lett ; 6(5): 523-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005526


Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25857941
J Med Chem ; 52(7): 1994-2005, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19267461


The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.

Compostos Heterocíclicos com 3 Anéis/síntese química , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/síntese química , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Cristalografia por Raios X , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Quinase I-kappa B/genética , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Oxazóis/farmacocinética , Oxazóis/farmacologia , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
Bioorg Med Chem Lett ; 15(11): 2728-33, 2005 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-15869878


In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.

Antibacterianos/química , Antibacterianos/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Animais , Haemophilus influenzae/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 14(18): 4735-9, 2004 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-15324898


A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.

Antibacterianos/síntese química , Isoxazóis/química , Nitrogênio/química , Oxazolidinonas/química , Oxazolona/análogos & derivados , Oxazolona/química , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Oxazolona/síntese química , Oxazolona/farmacologia , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 13(8): 1419-23, 2003 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-12668003


The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.

Antifúngicos/química , Antifúngicos/farmacocinética , Compostos Aza/síntese química , Compostos Aza/farmacocinética , Administração Oral , Animais , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Compostos Aza/química , Compostos Aza/farmacologia , Glicosídeos/química , Indenos , Injeções Intravenosas , Camundongos , Testes de Sensibilidade Microbiana , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 13(3): 519-24, 2003 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-12565963


Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.

Antifúngicos/síntese química , Antifúngicos/farmacologia , Aldeídos/síntese química , Aldeídos/química , Aldeídos/farmacologia , Alquilação , Diterpenos , Fungos/efeitos dos fármacos , Hidrólise , Indicadores e Reagentes , Testes de Sensibilidade Microbiana , Oxirredução , Relação Estrutura-Atividade