RESUMO
The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacos , Animais , Antivirais/química , Genótipo , Hepacivirus/genética , Humanos , Imidazóis/química , RatosRESUMO
The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.
Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Imidazóis/químicaRESUMO
Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Relação Estrutura-AtividadeRESUMO
The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.
Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Pirrolidinas/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacos , Antivirais/química , Benzimidazóis/química , Genótipo , Pirrolidinas/químicaRESUMO
Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the human H(3) receptor. The compounds exhibited up to a 60-fold preference for inhibiting the human H(3) receptor over the mouse and showed a low binding affinity for the hERG channel.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Cristalografia por Raios X , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Camundongos , Modelos Moleculares , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Pictet-Spengler condensation of aldehydes or alpha-keto-esters with 4-(2-anilinophenyl)-7-azaindole (11) or deazapurine (12) gave high yields of the 3,4-fused cyclic compounds. SAR studies, by varying the substituted benzaldehyde components, lead to the discovery of a series of potent JAK2 kinase inhibitors.
Assuntos
Indóis/química , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Purinas/química , Benzaldeídos/química , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Janus Quinase 2/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
CRTh2 (DP(2)) is a prostaglandin D(2) receptor implicated in the recruitment of eosinophils and basophils within the asthmatic lung. Here we report the discovery of a novel series of 3-indolyl sultam antagonists with low nM affinity for CRTh2. These compounds proved to be selective over the other primary prostaglandin D(2) receptor (DP1) as well as the thromboxane A(2) receptor (TP).
Assuntos
Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonamidas/farmacologia , Esterificação , Humanos , Sulfonamidas/químicaRESUMO
Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain in vivo models through a mechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A-O-demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a steric clash of the compound with the T5-loop of α-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite that binds to the colchicine site of tubulin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism.
Assuntos
Antineoplásicos/farmacologia , Noscapina/análogos & derivados , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Colchicina/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Noscapina/química , Noscapina/farmacologia , Ligação Proteica/efeitos dos fármacos , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 µM (1-2 µg/mL) against the H37Ra isolate of M. tuberculosis.
RESUMO
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
RESUMO
Blockade of presynaptic histamine H(3) receptors with potent and selective ligands improves cognitive function in rodents and there is significant interest in developing such drugs for long-term symptomatic treatment of CNS disorders such as attention deficit hyperactivity disorder (ADHD). Unfortunately, little is known about the effects of repeated exposure to H(3) receptor antagonists/inverse agonists. We therefore investigated the effects of acute and repeated daily administration of two potent, brain penetrating H(3) receptor antagonists/inverse agonists, ciproxifan and A-304121, on rat body weight, food and water intake, core temperature and locomotor activity, as well as H(3) receptor density and gene expression levels. Methylphenidate, used clinically for the treatment of ADHD, was included as an additional comparator. Ciproxifan, an imidazole-based compound, decreased food intake over the first 10 days and locomotor activity acutely, but these effects were lost after further repeated administration. The ex vivo binding studies revealed increased H(3) receptor density in rats following repeated administration of ciproxifan for 10 or 15 days; however, H(3) receptor gene expression was not changed. In contrast, rats treated with the non-imidazole, A-304121, did not differ from controls on any measure during the observation period, while rats treated with methylphenidate exhibited hyperthermia and hyperactivity. The implications for potential long-term treatment with H(3) receptor antagonists in CNS disorders such as ADHD are discussed.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Piperazinas/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Tolerância a Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/administração & dosagem , Imidazóis/administração & dosagem , Masculino , Metilfenidato/farmacologia , Atividade Motora/efeitos dos fármacos , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/biossíntese , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H3/genéticaRESUMO
H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H(3) receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H(3) receptor antagonists for the treatment of cognitive dysfunction.
Assuntos
Atenção/efeitos dos fármacos , Benzofuranos/farmacologia , Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Pirrolidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Administração Oral , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Benzofuranos/química , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Haplorrinos , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Memória/efeitos dos fármacos , Pirrolidinas/química , Ratos , Comportamento Social , Relação Estrutura-AtividadeRESUMO
Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.
Assuntos
Antineoplásicos/síntese química , Noscapina/análogos & derivados , Noscapina/síntese química , Fase S/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Noscapina/química , Noscapina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.
Assuntos
Antineoplásicos/síntese química , Noscapina/análogos & derivados , Noscapina/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biopolímeros , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Noscapina/farmacocinética , Noscapina/farmacologia , Estereoisomerismo , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
RESUMO
While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/química , Janus Quinase 3/antagonistas & inibidores , Valina/análogos & derivados , Animais , Linhagem Celular , Bases de Dados de Compostos Químicos , Cães , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Haplorrinos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Janus Quinase 2/química , Janus Quinase 3/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Valina/química , Valina/farmacocinética , Valina/farmacologiaRESUMO
Histamine H3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H3 receptor ligand, displaying high affinity for recombinant rat and human H3 receptors, with pKi values of 9.4 and 8.8, respectively, and high selectivity for the H3 receptor versus H1, H2, and H4 histamine receptors. A-349821 is a potent H3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pKb= 8.2 and pKb= 8.1, respectively), [35S]-GTPgammaS binding (pKb= 9.3 and pKb= 8.6, respectively) and calcium levels (human pKb= 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA2= 9.5) and histamine-mediated inhibition of [3H]-histamine release from rat brain cortical synaptosomes (pKb= 9.2). Additionally, A-349821 inhibited constitutive GTPgammaS binding at both rat and human H3 receptors with respective pEC50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-alpha-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10mg/kg, with the 1mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3mg/kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.
Assuntos
Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Cães , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Neurotransmissores/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Receptores Histamínicos H3/genética , Proteínas Recombinantes/antagonistas & inibidores , Radioisótopos de EnxofreRESUMO
Histamine H(3) receptor antagonists have been proposed as potentially useful therapeutic agents for the treatment of several disorders including attention deficit, schizophrenia, depression, and Alzheimer's disease. We have developed a repeated acquisition version of an inhibitory avoidance task using spontaneously hypertensive rat (SHR) pups that we believe provides a reproducible measure of the cognitive and attention deficits often characteristic of these disease states, and evaluated two H(3) receptor antagonists. Male SHR, Wistar (WI) and Wistar Kyoto (WKY) rat pups (20--24 days old) were trained to avoid a mild footshock (0.1 mA, 1 s duration), delivered when the pup had transferred from a brightly lit to a darkened compartment. After the first trial, the pup was removed and returned to its home cage. One minute later, the same pup was replaced in the brightly-lit compartment and the training process repeated. A total of five trials were recorded. SHR pups performed significantly more poorly than WI or WKY pups using this training schedule, and SHR pups were used for all subsequent studies. Methylphenidate and ABT-418, both clinically active in attention deficit hyperactivity disorder (ADHD), were tested to validate the model. Methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (0.03 mg/kg s.c.) significantly improved SHR pup performance. The H(3) receptor antagonists GT-2331 (1 mg/kg s.c.) and ciproxifan (3 mg/kg s.c.), also significantly, and in a dose-related manner, enhanced performance of the SHR pups. (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the pro-cognitive effects of ciproxifan, suggesting an H(3) receptor site of action for this compound. This model is useful for evaluating the cognition/attention-enhancing potential of H(3) receptor antagonists.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Nível de Alerta/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/farmacologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Comportamento Impulsivo/psicologia , Isoxazóis/farmacologia , Ligantes , Masculino , Metilfenidato/farmacologia , Atividade Motora/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.