RESUMO
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Assuntos
Acetamidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Piperazinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).
Assuntos
Amidas/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Técnicas de Química Sintética , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/química , Inibidores Enzimáticos/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
Assuntos
Aciltransferases/antagonistas & inibidores , Amidas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Aciltransferases/metabolismo , Amidas/química , Amidas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ensaios de Triagem em Larga Escala , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Assuntos
Acetamidas/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/uso terapêutico , Acetamidas/síntese química , Acetamidas/química , Animais , Cães , Concentração Inibidora 50 , Camundongos , Modelos Animais , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Coelhos , Ratos , Receptor B1 da Bradicinina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
Assuntos
Benzilaminas/química , Antagonistas de Receptor B1 da Bradicinina , Sulfonamidas/química , Tetra-Hidronaftalenos/química , Administração Oral , Animais , Dor/tratamento farmacológico , Ratos , Receptor B1 da Bradicinina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Assuntos
Antineoplásicos/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Tiadiazóis/química , Tiazóis/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Domínio Catalítico , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Neoplasias/tratamento farmacológico , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Assuntos
Antineoplásicos/química , Azóis/química , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Azóis/farmacocinética , Azóis/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
Assuntos
Ftalazinas/química , Ftalazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Desenho de Fármacos , Proteínas Hedgehog , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Ftalazinas/síntese química , Transdução de Sinais , Receptor SmoothenedRESUMO
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Ftalazinas/química , Piperazinas/química , Piridazinas/química , Receptores de Esteroides/química , Animais , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ftalazinas/síntese química , Ftalazinas/farmacocinética , Piperazinas/síntese química , Piperazinas/farmacocinética , Receptor de Pregnano X , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Esteroides/metabolismo , Transdução de Sinais , Receptor Smoothened , Relação Estrutura-Atividade , Tilosina/análogos & derivadosRESUMO
Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be â¼10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.
Assuntos
Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Quinolonas/farmacologia , Técnicas de Química Combinatória , Dipeptídeos/síntese química , Dipeptídeos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Estrutura Molecular , Pró-Colágeno-Prolina Dioxigenase/química , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A di-O-TBS protected glyceraldehyde synthon was condensed with Ellman's reagent to form a bench-stable N-tert-butanesulfinyl imine 6, which served as a common intermediate for the stereoselective introduction of various R groups. The Ellman adducts were converted to useful multifunctional intermediates 18a-i in one pot. The alcohols 18a-i were efficiently elaborated to both known and novel anti-N-protected-3-amino-1,2-epoxides in two steps. Compound 2a is a key intermediate toward HIV protease inhibitors.
Assuntos
Compostos de Epóxi/química , Compostos de Epóxi/síntese química , Gliceraldeído/química , Nitrogênio/química , Compostos de Sulfônio/química , Aminoácidos/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Benzamidas/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Macaca fascicularis , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridonas/síntese química , Quinazolinas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.
Assuntos
Acetamidas/síntese química , Antagonistas de Receptor B1 da Bradicinina , Química Farmacêutica/métodos , Quinoxalinas/síntese química , Receptor B1 da Bradicinina/química , Acetamidas/química , Ácido Acético/química , Aminas , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Isoxazóis/síntese química , Isoxazóis/farmacologia , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Isoxazóis/química , Conformação Molecular , Estrutura Molecular , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacosRESUMO
The LPA(2) protein is overexpressed in many tumor cells. We report the optimization of a series of LPA(2) antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA(2). Key compounds were evaluated in vitro for inhibition of LPA(2) mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA(2) inhibition both in vitro and in vivo.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Técnicas de Química Combinatória , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Antineoplásicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Células Tumorais CultivadasRESUMO
We report the structure-based design and synthesis of a novel series of aza-benzimidazoles as PHD2 inhibitors. These efforts resulted in compound 22, which displayed highly potent inhibition of PHD2 function in vitro.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Compostos Aza/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Benzimidazóis/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.