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


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.

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


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.

Bioorg Med Chem Lett ; 17(3): 679-82, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17098428


The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg).

Receptores de Quimiocinas/antagonistas & inibidores , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Camundongos , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores CCR4 , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologia , Relação Estrutura-Atividade
Bioorg Med Chem Lett ; 15(10): 2669-72, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15863339


The present study reports the identification and hits to leads optimization of chemokine receptor CCR4 antagonists. Compound 12 is a high affinity, non-cytotoxic antagonist of CCR4 that blocks the functional activity mediated by the receptor.

Receptores de Quimiocinas/antagonistas & inibidores , Receptores CCR4 , Receptores de Quimiocinas/fisiologia , Relação Estrutura-Atividade
J Org Chem ; 67(15): 5156-63, 2002 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-12126400


We have successfully effected a transfer of chirality from a chiral nonracemic allene to an alpha-alkylidene and an alpha-silylidene cyclopentenone. The molybdenum-mediated examples possessing a silyl group on the terminus of the allene show good facial selectivities, but isomerization of the (E)-silylidene cyclopentenone to the (Z)-silylidene cyclopentenone occurs upon purification of these products. Alternatively, an alkyl group on the terminus of the allene undergoes cycloaddition with moderate selectivities but gives products that undergo an isomerization of the (Z)-alkylidene cyclopentenone to the (E)-alkylidene cyclopentenone when exposed to acidic conditions. Thus, erosion of the enantiomeric excesses is observed for one of the two products as a result of this isomerization. The allenic Pauson-Khand-type cycloaddition has also been effected by first isolation the (eta(6)-arene)molybdenum tricarbonyl complex, demonstrating for the first time that this is most likely the active complex in the molybdenum-mediated reactions. Attempts to increase the facial selectivity by increasing the size of the arene moiety resulted in a marginal increase in the selectivity at the expense of the yield. Based upon these results, we have concluded that altering the approach for the preparation of nonracemic alpha-alkylidene cyclopentenones is necessary in order to obtain synthetically useful levels of stereocontrol.

Alcadienos/síntese química , Química Orgânica/métodos , Ciclopentanos/síntese química , Silanos/síntese química , Alcadienos/química , Catálise , Ciclização , Ciclopentanos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Molibdênio/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Silanos/química , Estereoisomerismo