RESUMO
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Assuntos
Antivirais/química , Hepacivirus/metabolismo , Indóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Área Sob a Curva , Genótipo , Meia-Vida , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Indóis/metabolismo , Indóis/farmacologia , Curva ROC , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Hepatite C/tratamento farmacológico , Imidazóis/síntese química , Imidazóis/química , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacocinética , Benzofuranos/química , Benzofuranos/farmacocinética , Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.
Assuntos
Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Tartaratos/química , Proteína ADAM17 , Amidas/síntese química , Amidas/química , Animais , Disponibilidade Biológica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , RatosRESUMO
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Assuntos
Receptor CB2 de Canabinoide/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonas/química , Sulfonas/síntese química , Animais , Canais de Cálcio/metabolismo , Sistema Enzimático do Citocromo P-450 , Agonismo Inverso de Drogas , Humanos , Piperidinas/química , Ratos , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/farmacocinéticaRESUMO
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Descoberta de Drogas , Inibidores de Proteases/química , Tartaratos/química , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17 , Sítios de Ligação , Técnicas de Química Combinatória , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Tartaratos/metabolismo , Tartaratos/farmacologiaRESUMO
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Proteína ADAM17 , Inibidores Enzimáticos/química , Hidantoínas/química , Ligação de Hidrogênio , Modelos Moleculares , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/química , Tartaratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Sítios de Ligação , Simulação por Computador , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/farmacocinéticaRESUMO
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteína ADAM17 , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/química , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteases/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Cães , Haplorrinos , Humanos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , RatosRESUMO
We have discovered nanomolar inhibitors of TNF-alpha convertase (TACE) comprised of a novel spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. X-ray crystal structures and computer models of selected compounds binding to TACE explain the observed SAR. We report the first TACE X-ray crystal structure for an inhibitor with a carboxylate zinc ligand.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Carboxílicos/química , Ácidos Hidroxâmicos/química , Proteína ADAM17 , Ácidos Carboxílicos/farmacologia , Simulação por Computador , Cristalografia por Raios X , Ácidos Hidroxâmicos/farmacologia , Ligantes , Modelos Moleculares , Ligação Proteica , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , ZincoRESUMO
INTRODUCTION: The cannabinoid type 2 receptor (CB(2) receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[(11)C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([(11)C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB(2) receptors. METHODS: Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [(11)C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [(11)C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined. RESULTS: [(11)C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/mumol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps. CONCLUSION: [(11)C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB(2) receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.
Assuntos
Radioisótopos de Carbono/química , Marcação por Isótopo , Ensaio Radioligante , Compostos Radiofarmacêuticos/síntese química , Receptor CB2 de Canabinoide/análise , Sulfonamidas/química , Animais , Barreira Hematoencefálica , Células CHO , Cricetinae , Cricetulus , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Camundongos , Compostos Radiofarmacêuticos/metabolismo , Sulfonamidas/metabolismo , Distribuição TecidualRESUMO
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Animais , Área Sob a Curva , Disponibilidade Biológica , Descoberta de Drogas , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacocinética , Modelos Moleculares , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
RESUMO
Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects a variety of cellular processes through both its actions as a second messenger and via activation of a family of G protein-coupled receptors (S1P(1-5)). The study of S1P receptor pharmacology, particularly S1P(4), has been hindered by the lack of high-affinity radioligands with good specific activity. The studies presented herein characterize [(3)H]DH-S1P as a stable, high-affinity radioligand for S1P(4) pharmacology. Using a transfected Ba/F3 cell line selected for high hS1P(4) surface expression, we compared the consequences of different cellular backgrounds and commercial sources of sphingophospholipids on S1P(4) characterization. The development and subsequent use of the assay described has enabled us to extensively and definitively characterize the pharmacology of the human S1P(4) receptor.
Assuntos
Fosfolipídeos/farmacologia , Receptores de Lisoesfingolipídeo/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Clonagem Molecular , Cricetinae , DNA Complementar/biossíntese , Citometria de Fluxo , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Ensaio Radioligante , Receptores de Superfície Celular/metabolismo , Receptores de Lisoesfingolipídeo/biossíntese , Receptores de Lisoesfingolipídeo/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Glicemia/metabolismo , Cicloexanonas/química , Cicloexanonas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica , Descoberta de Drogas , Glucagon/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Obesidade/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/metabolismo , Relação Estrutura-AtividadeRESUMO
Work to improve the therapeutic properties of cannabinoid CB(2) receptor-selective inverse agonists has led to the development of Sch.036, an aryl substituted triaryl bis-sulfone with improved oral pharmacokinetic parameters. In this report, we show that this compound blocks in vivo trafficking of various leukocyte populations, a property consistent with other members of this chemical series. This CB(2)-selective compound also shows efficacy in leukocyte recruitment models when added in concert with suboptimal doses of selected anti-inflammatory agents, consistent with its unique function and indicative of its potential therapeutic utility. Finally, studies with Sch.036 show that this cannabinoid CB(2)-specific inverse agonist can ameliorate bone damage in a rat model of relapsing-remitting arthritis. This result suggests that a cannabinoid CB(2)-selective inverse agonist may help ameliorate a particularly harmful property of this inflammatory joint disease.
Assuntos
Antígenos/toxicidade , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/prevenção & controle , Receptor CB2 de Canabinoide/agonistas , Sulfonas/farmacologia , Animais , Área Sob a Curva , Artrite Experimental/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Edema/tratamento farmacológico , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/imunologia , Indicadores e Reagentes , Ligantes , Lipopolissacarídeos , Camundongos , Pleurisia/induzido quimicamente , Pleurisia/prevenção & controle , Receptor CB1 de Canabinoide/agonistas , Sulfonas/uso terapêuticoRESUMO
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.