RESUMO
Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.
Assuntos
Amidas/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Animais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Assuntos
Amidas/química , Complemento C1s/antagonistas & inibidores , Desenho de Fármacos , Polietilenoglicóis/química , Inibidores de Proteases/síntese química , Tiofenos/química , Animais , Complemento C1s/metabolismo , Meia-Vida , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , RatosRESUMO
Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Benzimidazóis/química , Benzimidazóis/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Canais de Cátion TRPM/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Temperatura Baixa , Cães , Células HEK293 , Humanos , Ratos , Canais de Cátion TRPM/metabolismoRESUMO
A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazóis/síntese química , Piperidinas/síntese química , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Artrite Experimental/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Ratos , Ratos Endogâmicos Lew , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermoresponsive to cool to cold temperatures (8-28 °C) and also may be activated by chemical agonists such as menthol and icilin. Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia. The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels. Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain. Taken together, the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain.
Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Isoxazóis/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Constrição Patológica/tratamento farmacológico , Constrição Patológica/fisiopatologia , Cães , Células HEK293 , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Técnicas In Vitro , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Ratos , Relação Estrutura-AtividadeRESUMO
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.
Assuntos
Amidas/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
Assuntos
Anticoagulantes/síntese química , Fibrinolíticos/síntese química , Guanidinas/síntese química , Pirazinas/síntese química , Trombina/antagonistas & inibidores , Motivos de Aminoácidos , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CACO-2 , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Método Duplo-Cego , Eletrocardiografia , Feminino , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Guanidinas/farmacocinética , Guanidinas/farmacologia , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/química , Trombose Venosa/sangue , Trombose Venosa/tratamento farmacológicoRESUMO
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Imidazóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/enzimologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Ratos , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/sangue , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.
Assuntos
Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Fenilenodiaminas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Simulação por Computador , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
Assuntos
Macrófagos/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Polarização de Fluorescência , Genes fos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Quinolonas/farmacocinética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Relação Estrutura-AtividadeRESUMO
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Assuntos
Complemento C1s/antagonistas & inibidores , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Sítios de Ligação , Meia-Vida , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Colágeno , Relação Dose-Resposta a Droga , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
Assuntos
Acridinas/síntese química , IMP Desidrogenase/antagonistas & inibidores , Piperazinas/síntese química , Acridinas/farmacologia , Acridinas/toxicidade , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Linhagem Celular , Proliferação de Células , Trato Gastrointestinal/efeitos dos fármacos , Meia-Vida , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Macaca fascicularis , Masculino , Piperazinas/farmacologia , Piperazinas/toxicidade , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
Assuntos
Sulfonatos de Arila/síntese química , Complemento C1s/antagonistas & inibidores , Inibidores de Serina Proteinase/síntese química , Amidinas/síntese química , Amidinas/farmacologia , Angioedema/tratamento farmacológico , Sulfonatos de Arila/farmacologia , Fibrinolisina/farmacologia , Rejeição de Enxerto/tratamento farmacológico , Humanos , Isquemia Miocárdica/tratamento farmacológico , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Trombina/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/farmacologiaRESUMO
A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Catálise , Cinética , Relação Estrutura-AtividadeRESUMO
The development of a series of novel indole-based inhibitors of 5'-inosine monophosphate dehydrogenase (IMPDH) is described. Various hydrogen bond acceptors at C-3 of the indole were explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are outlined.