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1.
ChemMedChem ; 15(16): 1562-1570, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32613743

RESUMO

Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Relação Estrutura-Atividade , Quinases Dyrk
2.
J Med Chem ; 63(6): 2958-2973, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32077280

RESUMO

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).


Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Compostos Aza/farmacocinética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Quinases Dyrk
3.
Org Lett ; 21(3): 816-820, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673257

RESUMO

A one-pot electrochemical nickel-catalyzed decarboxylative sp2-sp3 cross-coupling reaction has been developed using redox-active esters prepared in situ from alkyl carboxylates and  N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (PITU). This undivided cell one-pot method enables C-C bond formation using inexpensive, benchtop-stable reagents with isolated yields up to 95% with good functional group tolerance, which includes nitrile, ketone, ester, alkene and selectivity over other aromatic halogens.

4.
Org Lett ; 20(23): 7429-7432, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30427201

RESUMO

A versatile flow synthesis method for in situ formation of organozinc reagents and subsequent cross-coupling with aryl halides and activated carboxylic acids is reported. Formation of organozinc reagents is achieved by pumping organic halides, in the presence of ZnCl2 and LiCl, through an activated Mg-packed column under flow conditions. This method provides efficient in situ formation of aryl, primary, secondary, and tertiary alkyl organozinc reagents, which are subsequently telescoped downstream to a Negishi or decarboxylative Negishi cross-coupling reaction. The described method offers access to a variety of C-C bond formations with organozinc reagents that are otherwise commercially unavailable or difficult to prepare under traditional batch reaction conditions.

5.
Chembiochem ; 19(8): 799-804, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29388367

RESUMO

Activated esters are widely used to label proteins at lysine side chains and N termini. These reagents are useful for labeling virtually any protein, but robust reactivity toward primary amines generally precludes site-selective modification. In a unique case, fluorophenyl esters are shown to preferentially label human kappa antibodies at a single lysine (Lys188) within the light-chain constant domain. Neighboring residues His189 and Asp151 contribute to the accelerated rate of labeling at Lys188 relative to the ≈40 other lysine sites. Enriched Lys188 labeling can be enhanced from 50-70 % to >95 % by any of these approaches: lowering reaction temperature, applying flow chemistry, or mutagenesis of specific residues in the surrounding protein environment. Our results demonstrated that activated esters with fluoro-substituted aromatic leaving groups, including a fluoronaphthyl ester, can be generally useful reagents for site-selective lysine labeling of antibodies and other immunoglobulin-type proteins.


Assuntos
Lisina/metabolismo , Proteínas/metabolismo , Cristalografia por Raios X , Teoria da Densidade Funcional , Humanos , Conformação Proteica , Proteínas/química , Termodinâmica
6.
J Med Chem ; 59(17): 7901-14, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27502700

RESUMO

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Administração por Inalação , Animais , Linhagem Celular , Proliferação de Células , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Membranas Artificiais , Simulação de Acoplamento Molecular , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Permeabilidade , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/química , Pirazóis/síntese química , Pirazóis/farmacologia , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/química , Receptores do Fator de Crescimento Derivado de Plaquetas/química , Relação Estrutura-Atividade
7.
ACS Med Chem Lett ; 6(5): 562-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005534

RESUMO

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

8.
Cancer Chemother Pharmacol ; 75(1): 131-41, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25394774

RESUMO

PURPOSE: Neuroblastoma (NB) is one of the most common and deadly pediatric solid tumors. NB is characterized by clinical heterogeneity, from spontaneous regression to relentless progression despite intensive multimodality therapy. There is compelling evidence that members of the tropomyosin receptor kinase (Trk) family play important roles in these disparate clinical behaviors. Indeed, TrkB and its ligand, brain-derived neurotrophic factor (BDNF), are expressed in 50-60 % of high-risk NBs. The BDNF/TrkB autocrine pathway enhances survival, invasion, metastasis, angiogenesis and drug resistance. METHODS: We tested a novel pan-Trk inhibitor, GNF-4256 (Genomics Institute of the Novartis Research Foundation), in vitro and in vivo in a nu/nu athymic xenograft mouse model to determine its efficacy in inhibiting the growth of TrkB-expressing human NB cells (SY5Y-TrkB). Additionally, we assessed the ability of GNF-4256 to enhance NB cell growth inhibition in vitro and in vivo, when combined with conventional chemotherapeutic agents, irinotecan and temozolomide (Irino-TMZ). RESULTS: GNF-4256 inhibits TrkB phosphorylation and the in vitro growth of TrkB-expressing NBs in a dose-dependent manner, with an IC50 around 7 and 50 nM, respectively. Furthermore, GNF-4256 inhibits the growth of NB xenografts as a single agent (p < 0.0001 for mice treated at 40 or 100 mg/kg BID, compared to controls), and it significantly enhances the antitumor efficacy of irinotecan plus temozolomide (Irino-TMZ, p < 0.0071 compared to Irino-TMZ alone). CONCLUSIONS: Our data suggest that GNF-4256 is a potent and specific Trk inhibitor capable of significantly slowing SY5Y-TrkB growth, both in vitro and in vivo. More importantly, the addition of GNF-4256 significantly enhanced the antitumor efficacy of Irino-TMZ, as measured by in vitro and in vivo growth inhibition and increased event-free survival in a mouse xenograft model, without additional toxicity. These data strongly suggest that inhibition of TrkB with GNF-4256 can enhance the efficacy of current chemotherapeutic treatment for recurrent/refractory high-risk NBs with minimal or no additional toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Drogas em Investigação/farmacologia , Meia-Vida , Humanos , Irinotecano , Glicoproteínas de Membrana/metabolismo , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neuroblastoma/sangue , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Receptor trkB , Análise de Sobrevida , Temozolomida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Expert Opin Ther Pat ; 23(10): 1317-35, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23826715

RESUMO

INTRODUCTION: The development of small molecule agonists of the liver X receptors (LXRs) has been an area of interest for over a decade, given the critical role of those receptors in cholesterol metabolism, glucose homeostasis, inflammation, innate immunity and lipogenesis. Many potential indications have been characterized over time including atherosclerosis, diabetes, inflammation, Alzheimer's disease and cancer. However, concerns about the lipogenic effects of full LXRα/ß agonists have required extensive efforts aimed at identifying LXRß agonist with limited activity on the LXRα receptor to increase the safety margins. AREAS COVERED: This review includes a summary of the LXR agonists that have reached the clinic and summarizes the patent applications for LXR modulators from September 2009 to December 2012 with emphasis on chemical matters, biological data associated with selected analogs and therapeutic indications. EXPERT OPINION: As LXR agonists have the potential to be useful for many indications, the scientific community, despite setbacks due to on-target side effects, has maintained interest and devised strategies to overcome safety hurdles. While a clinical proof of concept still remains elusive, the recent advancement of compounds into the clinic highlights that acceptable safety margins in preclinical species have been achieved.


Assuntos
Fígado/metabolismo , Receptores Nucleares Órfãos/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Aprovação de Drogas , Indústria Farmacêutica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptores X do Fígado , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/antagonistas & inibidores , Patentes como Assunto
10.
ACS Med Chem Lett ; 3(2): 140-5, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900443

RESUMO

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.

11.
Chem Commun (Camb) ; 47(34): 9588-90, 2011 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-21607236

RESUMO

A D(3)-symmetric knotted cyclophane, with a subgraph of trefoil topology, was synthesized by cyclization of a D(3)-symmetric scaffold. Control of configuration at the three metal-based stereocenters arises from a bascule/pivot mechanism.


Assuntos
Técnicas de Química Sintética , Éteres Cíclicos/química , Éteres Cíclicos/síntese química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
12.
Org Biomol Chem ; 3(17): 3105-16, 2005 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-16106292

RESUMO

Concatenated macrocycles containing manisyl-substituted tridentate ligands 2,2':6',2''-terpyridine and 2-pyridin-2-yl-1,10-phenanthroline (simply referred to as terpyridine and pyridyl-phenanthroline herein) have been prepared via dual cyclization procedures. The manisyl derivative (manisyl = 4-methoxy-2,6-dimethylphenyl) was chosen for its ability to improve solubility while simultaneously incorporating functionality. Deprotection of the methoxy groups provided a soluble ligand that was re-alkylated with an array of terminal alkyne and alkene linkers. The tridentate coordinating ability of these ligands enabled complexation with Ru(ii) and Fe(ii), generating achiral and racemic octahedral complexes for terpyridine and pyridyl-phenanthroline, respectively. Subsequent macrocyclization via olefin metathesis or copper-mediated alkyne coupling afforded the corresponding catenanes, and in some cases a figure-eight macrocycle. The difference in symmetry and the presence of the manisyl group allowed the distinction between the catenane and the undesired figure-eight to be made directly by (1)H NMR. Metal-free achiral and racemic catenanes were obtained by liberating Fe(ii) from the octahedral bound title ligands by treatment with hydrogen peroxide.


Assuntos
Catenanos/síntese química , Mimetismo Molecular , Compostos Organometálicos/síntese química , Fenantrolinas/química , Piridinas , Catenanos/química , Cristalografia por Raios X , Ciclização , Ferro/química , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Rutênio/química , Estereoisomerismo
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