RESUMO
The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Oxazolidinonas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Avaliação Pré-Clínica de Medicamentos , Transferência Ressonante de Energia de Fluorescência , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazolidinonas/química , Relação Estrutura-AtividadeRESUMO
Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/fisiologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Humanos , Terapia de Alvo Molecular , Compostos de Espiro/síntese químicaRESUMO
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Humanos , Conformação Molecular , Dados de Sequência Molecular , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Assuntos
Isoxazóis/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Sítios de Ligação , Glicemia/metabolismo , Cristalografia por Raios X , Diabetes Mellitus Experimental/metabolismo , Cães , Transferência Ressonante de Energia de Fluorescência , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Ligantes , Camundongos , Conformação Molecular , Estrutura Terciária de Proteína , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
Assuntos
Compostos de Boro/química , Ácidos Borônicos/química , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítios de Ligação , Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Hepacivirus/efeitos dos fármacos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Assuntos
Isoxazóis/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Isoxazóis/química , Isoxazóis/farmacologia , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-AtividadeRESUMO
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Assuntos
Isoxazóis/química , Naftalenos/química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiofenos/química , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Humanos , Isoxazóis/farmacologia , Naftalenos/farmacocinética , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
Development of an efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand, allowed its biological and physical properties to be studied. FICZ was shown to be the most potent among a series of 6-substituted indolo[3,2-b]carbazoles for activation of AhR in cells. Photostability studies of FICZ revealed a non-enzymatic mechanism for its conversion to a biologically active quinone. These results further support the hypothesis that FICZ is a light-dependent hormone that links sun exposure to regulation of biological pathways in peripheral tissues.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carbazóis/síntese química , Receptores de Hidrocarboneto Arílico/metabolismo , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Processos FotoquímicosRESUMO
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Colestase/tratamento farmacológico , Proteínas de Ligação a DNA/agonistas , Isoxazóis/síntese química , Isoxazóis/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Administração Oral , Animais , Ácidos Carboxílicos/química , Colestase/metabolismo , Colestase/patologia , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Modelos Animais de Doenças , Cães , Mucosa Gástrica/metabolismo , Haplorrinos , Isoxazóis/química , Camundongos , Conformação Molecular , Estrutura Molecular , Naftalenos/química , Ratos , Receptores Citoplasmáticos e Nucleares/química , Estômago/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/químicaRESUMO
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.
Assuntos
Fármacos Anti-HIV/síntese química , Farmacorresistência Viral , Transcriptase Reversa do HIV/química , Quinolonas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Alcinos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzoxazinas , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Ciclopropanos , Desenho de Fármacos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Oxazinas/química , Quinolonas/química , Quinolonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
GW4511, GW4751, and GW3011 showed IC50 values < or =2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.
Assuntos
Fármacos Anti-HIV/síntese química , Benzofenonas/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Linhagem Celular , Cristalografia por Raios X , Farmacorresistência Viral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Concentração Inibidora 50 , Mutação , Ligação Proteica , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIIIα is an essential component of these replication organelles. RNA interference of PI4KIIIα results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIIIα is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients. We investigated if small molecule inhibitors of PI4KIIIα could inhibit HCV replication in vitro. The synthesis and structure-activity relationships associated with the biological inhibition of PI4KIIIα and HCV replication are described. These efforts led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Animais , Antivirais/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Modelos Animais de Doenças , Hepacivirus/fisiologia , Hepatite C/virologia , Camundongos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologiaRESUMO
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.
RESUMO
A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir.
Assuntos
Herpesviridae/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Piridinas/síntese química , Piridinas/toxicidade , Relação Estrutura-AtividadeRESUMO
Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Fenol/química , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Pirazóis/química , Piridinas/química , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage intermediates. Detailed examination of the amine substituents at the C2' position of the pyrimidine and C7 position of the core pyrazolopyridine is described. The antiviral data suggests that non-polar amines are preferred for optimal activity. Additionally, the 2' position has been shown to require an NH group to retain activity levels similar to that of the gold standard acyclovir.
Assuntos
Aminas/química , Antivirais/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Chlorocebus aethiops , Herpesviridae/efeitos dos fármacos , Herpesvirus Cercopitecino 1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Células VeroRESUMO
Gugulipid is an extract of the guggul tree, Commiphora mukul, that is used to treat hyperlipidemia in humans. The lipid-lowering activity is found in the stereoisomers and plant sterols Z-guggulsterone and E-guggulsterone. The molecular basis for the lipid-lowering action of guggulsterone has been suggested to be antagonism of the farnesoid X receptor, a member of the nuclear receptor superfamily of ligand-activated transcription factors. To determine whether guggulsterone has the ability to function as an agonist of other nuclear receptor family members, we screened a panel of these proteins for their ability to transactivate reporter genes. Here, we show that guggulsterones activate the estrogen receptor alpha isoform, progesterone receptor, and pregnane X receptor. Concentration-response analysis using reporter gene assays indicate that guggulsterones activate these three receptors with EC(50) values in the low micromolar range. Furthermore, we show that guggulsterone-mediated activation of the pregnane X receptor induces the expression of CYP3A genes in both rodent and human hepatocytes. Protein interaction assays indicate that guggulsterones interact directly with pregnane X receptor, thereby modulating interaction with protein cofactors. We introduce a novel method to screen herbal remedies for their ability to activate pregnane X receptor. Pregnane X receptor activation is known to cause herb-drug interactions, and our data suggest that gugulipid therapy should be used cautiously in patients taking prescription medications that are metabolized by CYP3A family members. Moreover, our data suggest the need for additional studies of guggulsterones agonist activity against estrogen receptor alpha isoform and the progesterone receptor.