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1.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682

RESUMO

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

2.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

4.
Org Lett ; 11(20): 4672-5, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19810767

RESUMO

A short synthesis of the natural product epi-citreodiol and the method developed to gain access to this target are described. Key advances focus on silyl substituted allenes. Upon exposure to dimethyldioxirane, spirodiepoxides form with high face selectivity and subsequently react at the silyl terminus.


Assuntos
Compostos de Epóxi/química , Compostos de Espiro/química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
5.
J Org Chem ; 74(20): 7707-14, 2009 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-19761213

RESUMO

Three closely related analogues of epoxomicin have been synthesized. Allene-derived spirodiepoxides were key intermediates. Spirodiepoxide formation and stereochemical dependence on solvent, oxidant, and allene structure were cataloged. The facial selectivity of the first epoxidation of 1,3-disubstituted and trisubstituted allenes was found to be >20:1 with dimethyldioxirane in chloroform. For stereogenic allenes, the facial selectivity of the second oxidation is dependent primarily on allene structure and secondarily on solvent and oxidant. For the acyclic systems evaluated this ratio was as high as 8:1. A conformational model is advanced to account for these observations.


Assuntos
Compostos de Espiro/química , Modelos Químicos , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Estereoisomerismo
6.
J Med Chem ; 49(15): 4785-9, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854086

RESUMO

Compounds containing a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2H-1-benzopyran and a 3-alkylindole moiety linked through a common basic nitrogen were prepared and evaluated for 5-HT1A affinity, serotonin rat transporter affinity, and functional antagonist activity in vitro. 26a was found to be the most potent and selective compound in this series and was shown to possess neurochemical activity in vivo by producing acute and rapid increases in 5-HT in the rat frontal cortex.


Assuntos
Antidepressivos/síntese química , Benzopiranos/síntese química , Cromanos/síntese química , Indóis/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/síntese química , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Células CHO , Cromanos/química , Cromanos/farmacologia , Cricetinae , Cricetulus , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Microdiálise , Ensaio Radioligante , Ratos , Serotonina/biossíntese , Agonistas do Receptor 5-HT1 de Serotonina , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
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