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1.
Science ; 352(6288): aad3018, 2016 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-27199435

RESUMO

Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzotiazóis/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias Experimentais/terapia , Ácidos Picolínicos/uso terapêutico , Pirazinas/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Microambiente Tumoral/imunologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzotiazóis/farmacologia , Glioblastoma/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/farmacologia , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos , Fatores de Transcrição NFATC/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Experimentais/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Ácidos Picolínicos/farmacologia , Pirazinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais
2.
Nat Med ; 19(10): 1264-72, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24056773

RESUMO

Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Macrófagos/citologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Neoplasias Encefálicas/metabolismo , Progressão da Doença , Glioblastoma/metabolismo , Camundongos , Transdução de Sinais
3.
Bioorg Med Chem Lett ; 23(18): 5239-43, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23927973

RESUMO

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.


Assuntos
Ácidos Carboxílicos/química , Descoberta de Drogas , Fator VIIa/antagonistas & inibidores , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Benzamidinas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fator VIIa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Relação Estrutura-Atividade
4.
J Med Chem ; 52(9): 2794-8, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19351168

RESUMO

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.


Assuntos
Androgênios , Músculos/efeitos dos fármacos , Músculos/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Animais , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio , Masculino , Modelos Moleculares , Conformação Molecular , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ratos , Especificidade por Substrato
5.
Bioorg Med Chem Lett ; 18(11): 3168-72, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18485702

RESUMO

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 17(23): 6476-80, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17937986

RESUMO

The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.


Assuntos
Dipeptídeos/química , Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/química , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Nitrilos/química , Nitrilos/farmacologia , Relação Estrutura-Atividade
8.
J Med Chem ; 50(13): 3015-25, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17552509

RESUMO

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.


Assuntos
Anabolizantes/síntese química , Imidazóis/síntese química , Músculo Esquelético/efeitos dos fármacos , Pirróis/síntese química , Receptores Androgênicos/metabolismo , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Meia-Vida , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Músculo Esquelético/anatomia & histologia , Orquiectomia , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 14(9): 2227-31, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15081014

RESUMO

Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.


Assuntos
Azetidinas/síntese química , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serino Proteinase/síntese química , Azetidinas/química , Azetidinas/farmacologia , Humanos , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Triptases
10.
Bioorg Med Chem Lett ; 14(9): 2233-9, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15081015

RESUMO

A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.


Assuntos
Azetidinas/síntese química , Azetidinas/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Azetidinas/química , Cristalografia por Raios X , Modelos Moleculares , Serina Endopeptidases/química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Triptases
11.
Bioorg Med Chem Lett ; 14(2): 309-12, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14698147

RESUMO

The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].


Assuntos
Azepinas/síntese química , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/síntese química , Azepinas/farmacologia , Humanos , Inibidores de Serino Proteinase/farmacologia , Triptases
12.
Bioorg Med Chem Lett ; 12(21): 3229-33, 2002 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-12372540

RESUMO

A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.


Assuntos
Antiasmáticos/síntese química , Antiasmáticos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Animais , Asma/tratamento farmacológico , Asma/patologia , Broncoconstrição/efeitos dos fármacos , Cristalografia por Raios X , Espaço Extracelular/efeitos dos fármacos , Cobaias , Meia-Vida , Humanos , Inflamação/patologia , Pulmão/patologia , Conformação Molecular , Ovalbumina/imunologia , Relação Estrutura-Atividade , Triptases
13.
Bioorg Med Chem Lett ; 12(21): 3235-8, 2002 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-12372541

RESUMO

The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.


Assuntos
Antiasmáticos/síntese química , Antiasmáticos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Aziridinas/síntese química , Aziridinas/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/farmacologia , Animais , Asma/tratamento farmacológico , Asma/imunologia , Estabilidade de Medicamentos , Cobaias , Humanos , Ovalbumina/imunologia , Estereoisomerismo , Relação Estrutura-Atividade , Triptases
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