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1.
ACS Med Chem Lett ; 10(10): 1486-1491, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31620238

RESUMO

C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1, and a series of modifications led to optimized compound 13. Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose.

3.
ACS Med Chem Lett ; 6(5): 523-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005526

RESUMO

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.

4.
Bioorg Med Chem Lett ; 25(9): 1905-9, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25857941
5.
Bioorg Med Chem Lett ; 21(2): 781-5, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21177105
6.
J Med Chem ; 52(21): 6527-30, 2009 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-19821562

RESUMO

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.


Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macaca fascicularis , Camundongos , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologia
8.
Clin Cancer Res ; 12(20 Pt 1): 6186-93, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17062696

RESUMO

PURPOSE: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression. RESULTS: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. CONCLUSIONS: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.


Assuntos
Antineoplásicos/toxicidade , Inibidores Enzimáticos/toxicidade , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Antígenos CD8/imunologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Dimerização , Humanos
10.
Bioorg Med Chem Lett ; 15(24): 5478-82, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16216508

RESUMO

A 3D quantitative structure-activity relationship study for inhibition of calcium-sensing receptor in the aryloxypropanolamine series predicted that these molecules adopt a U-shaped conformation with pi-stacking between the two aromatic rings. This hypothesis led to the discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines capable of antagonizing the calcium-sensing receptor with potency comparable to that of NPS-2143.


Assuntos
Receptores de Detecção de Cálcio/antagonistas & inibidores , Etanolaminas/síntese química , Etanolaminas/química , Etanolaminas/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Osteoporose/tratamento farmacológico , Conformação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores de Detecção de Cálcio/química , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 15(17): 3816-20, 2005 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15993593

RESUMO

A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropanolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series.


Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Propanolaminas/química , Relação Quantitativa Estrutura-Atividade , Animais , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Propanolaminas/farmacologia , Especificidade por Substrato
12.
J Comb Chem ; 7(1): 99-108, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15638488

RESUMO

Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Aminas/química , Benzeno/química , Iminas/química , Zinco/química , Agonistas Adrenérgicos beta/química , Técnicas de Química Combinatória , Estrutura Molecular , Relação Estrutura-Atividade
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