RESUMO
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
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
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
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
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
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
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
This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and ß-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.
Assuntos
Produtos Biológicos/química , Desenho de Fármacos , Analgésicos Opioides/química , Animais , Antibacterianos/química , Técnicas de Química Sintética , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Macrolídeos/química , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Peptídeos/química , Solubilidade , Solventes , Esteroides/química , Relação Estrutura-Atividade , Taxoides/químicaRESUMO
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
Assuntos
Antivirais/química , Compostos Aza/química , Indóis/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/síntese química , Antivirais/farmacologia , Compostos Aza/síntese química , Compostos Aza/farmacologia , Disponibilidade Biológica , Cães , Farmacorresistência Viral , Indóis/síntese química , Indóis/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Infecções por Orthomyxoviridae/tratamento farmacológico , Ratos , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.
RESUMO
Noscapine and its 7-hydroxy and 7-amino derivatives were characterized for their binding to tubulin. A solution NMR structure of these compounds bound to tubulin shows that noscapine and its 7-aniline derivative do not compete for the same binding site nor does its small molecule crystal structure match its tubulin-bound conformation. These compounds were also tested for their antiproliferative effects on a panel hepatocellular carcinoma cell lines.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Noscapina/análogos & derivados , Noscapina/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Noscapina/farmacologia , Ligação Proteica , Soluções , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologiaRESUMO
Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs.
RESUMO
Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs.
Assuntos
Descoberta de Drogas/tendências , Indústria Farmacêutica/tendências , Necessidades e Demandas de Serviços de Saúde/tendências , Animais , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , HumanosRESUMO
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
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
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
The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.