Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-30373802

RESUMO

Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial Type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double strand cleavages in bacteria. We report results from two Phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin, and the absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed with a Tmax between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg, and less than dose proportionally between 800 and 4000 mg. Urinary excretion of unchanged zoliflodacin was >5.0% of the total dose. In the fed state, absorption was delayed (Tmax 4 h), accompanied by an increase in the AUC at 1500 and 3000 mg doses. In the ADME study (3000 mg PO), the PK profile of zoliflodacin had similar exposure (AUC and Cmax) to the ascending dose study and a median Tmax of 2.5 hours. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon the safety, PK, and the PK/PD targets, a dosage regimen was selected for evaluation in a Phase 2 study in urogenital gonorrhea.

2.
J Med Chem ; 61(4): 1622-1635, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29400470

RESUMO

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.

3.
Xenobiotica ; 47(11): 962-972, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27754725

RESUMO

1. During the course of metabolic profiling of lead Compound 1, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and N-acetylcysteine (NAC) conjugates in microsomal incubations. 2. It was proposed that bioactivation of Compound 1 occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core. 3. To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC. 4. Compounds 1 and 2, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates in vitro, whereas compounds with tertiary nitrogens at C-5 (Compound 3 and 4) formed no such conjugates. 5. These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound 3 and 4 incapable of forming thiol conjugates. 6. This finding enabled advancement of compound 4, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.


Assuntos
Antimaláricos/metabolismo , Acetilcisteína/metabolismo , Animais , Bile/metabolismo , Biotransformação , Glutationa/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Quinonas , Ratos , Compostos de Sulfidrila/metabolismo
4.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

5.
J Med Chem ; 58(23): 9273-86, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26568411

RESUMO

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Administração Oral , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Animais , Corioide/efeitos dos fármacos , Corioide/patologia , Neovascularização de Coroide/patologia , Feminino , Humanos , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Degeneração Macular Exsudativa/patologia
6.
Drug Metab Dispos ; 43(10): 1441-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26203069

RESUMO

This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an (18)O atom from molecular (18)O2 to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or l-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.


Assuntos
Peróxidos Lipídicos/sangue , Proteínas Secretadas Inibidoras de Proteinases/sangue , Proteínas Secretadas Inibidoras de Proteinases/química , Amidas/sangue , Amidas/química , Animais , Feminino , Humanos , Peróxidos Lipídicos/química , Masculino , Oxirredução , Pirazinas/sangue , Pirazinas/química , Pirazóis/sangue , Pirazóis/química , Ratos , Ratos Wistar
7.
Nat Commun ; 6: 6715, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25823686

RESUMO

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacologia , Aminas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Cobaias , Meia-Vida , Ratos
8.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25686852

RESUMO

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.


Assuntos
Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Pirrolidinas/química , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Camundongos Obesos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
9.
Chem Res Toxicol ; 27(9): 1586-97, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25126895

RESUMO

Reactive metabolites (RMs) have been implicated as causal factors in many drug-associated idiosyncratic toxicities. This study aims at identification and mitigation of an RM liability associated with aminoimidazole and amino(aza)benzimidazole structural motifs from an antimalarial project. Nineteen compounds with different structural modifications were studied in rat and human liver microsomes using glutathione (GSH) and N-acetyl cysteine (NAC) as trapping agents for RM. Metabolite profiling of aminoimidazole compounds in initial studies revealed the presence of dihydrodiol metabolites suggestive of reactive epoxide precursors, confirmed by the identification of a dihydrohydroxy GSH conjugate in GSH supplemented incubations. Substitution of methyl group at a potential site of metabolism blocked the epoxidation; however, formation of an imine-methide RM was suspected. Masking the site of metabolism via benzimidazole and 4/7-azabenzimidazole resulted in the possible formation of quinone-imine intermediates as a product of bioactivation. Further, substitutions with electron withdrawing groups and steric crowding did not address this liability. Mitigation of bioactivation was achieved with 5/6-azabenzimidazole and with CF3 substitution at the 6-position of the 7-azabenzimidazole ring. Moreover, compounds devoid of imidazole -NH2 do not undergo bioactivation. This study, therefore, establishes aminoimidazole and amino(aza)benzimidazoles as potential toxicophores and describes ways to mitigate this bioactivation liability by chemical modification.


Assuntos
Benzimidazóis/metabolismo , Animais , Compostos Aza/química , Benzimidazóis/análise , Cromatografia Líquida de Alta Pressão , Iminas/química , Quinonas/química , Ratos , Espectrometria de Massas em Tandem
10.
J Med Chem ; 57(15): 6642-52, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25007124

RESUMO

From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.


Assuntos
Aminopiridinas/química , Antimaláricos/química , Benzimidazóis/química , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Hepatócitos/metabolismo , Humanos , Malária/tratamento farmacológico , Malária/mortalidade , Camundongos SCID , Microssomos Hepáticos/metabolismo , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
11.
J Med Chem ; 57(13): 5702-13, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24914738

RESUMO

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.


Assuntos
Antimaláricos/farmacologia , Benzimidazóis/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Camundongos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
12.
J Med Chem ; 57(11): 4761-71, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24818517

RESUMO

A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl-ß-D-ribose-2'-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.


Assuntos
Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirazóis/síntese química , Piridonas/síntese química , Oxirredutases do Álcool , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Domínio Catalítico , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutação , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/isolamento & purificação , Oxirredutases/genética , Pirazóis/química , Pirazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Relação Estrutura-Atividade
13.
J Med Chem ; 57(12): 5419-34, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24871036

RESUMO

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.


Assuntos
Amidas/química , Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Piperidinas/química , Quinolonas/química , Oxirredutases do Álcool , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Farmacorresistência Bacteriana , Genoma Bacteriano , Humanos , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutação , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Med Chem ; 56(23): 9701-8, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24215368

RESUMO

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-ß-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Indóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases do Álcool , Animais , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Indóis/farmacocinética , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Ratos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
16.
Eur J Pharm Sci ; 49(1): 33-8, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-23395915

RESUMO

The discovery of novel therapeutics for the treatment of tuberculosis involves routine testing in a mouse model over four weeks of daily dosing with test compounds. In this model, daily oral administration of rifampin (10 mg/kg) showed significantly lower plasma exposure on day 5 compared to day 1. The absence of PXR-mediated induction of mouse Cyp3a isoforms was confirmed in the present study by incubating liver microsomes prepared from control and rifampin treated mice with probe substrates of CYP3A. To test whether the reduction in exposure was due to Pgp-mediated efflux, verapamil, a known Pgp inhibitor, was dosed to the rifampin pre-treated mice which led to an increase in exposure to that obtained after a single dose of rifampin, suggesting the role of Pgp induction in reducing exposure to rifampin. To further confirm Pgp induction in rifampin treated mice, digoxin, a known substrate of Pgp, was administered to the rifampin pre-treated mice, and a significant drop in the digoxin exposure was observed compared to the control group. Collectively, our results show that repeated administration of rifampin in mice leads to a reduction in oral exposure due to induction of Pgp-mediated efflux of rifampin, and not via induction of CYP3A isoforms.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Rifampina/administração & dosagem , Rifampina/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Rifampina/sangue , Fatores de Tempo
17.
Bioorg Med Chem Lett ; 21(5): 1447-51, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21300545

RESUMO

The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling.


Assuntos
Azóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Azóis/síntese química , Azóis/química , Azóis/farmacocinética , Disponibilidade Biológica , Histona Desacetilases/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade
18.
Drug Metab Pharmacokinet ; 26(1): 102-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21084760

RESUMO

Standard incubation procedures for carrying out microsomal assays involve the use of less than 1% w/v organic solvents to minimize the potential inhibitory effects of organic solvents on metabolic activity. This presents a practical limitation for poorly soluble xenobiotics, which cannot be incubated at concentrations high enough to obtain a V(max), and therefore subsequent values for K(m) and Cl(int) cannot be calculated. Our goal was to study the application of a variety of pharmaceutical excipients to aid the solubilization of compounds in vitro in glucuronidation incubations, without affecting the reaction kinetics. In vitro glucuronidation incubations were carried out in human liver microsomes with 4-methylumbelliferone (4-MU) and the kinetics of 4-MU glucuronidation in the presence of excipients were compared to that in control incubations without any excipients. In addition, IC(75) values were calculated for each excipient. We observed that HPBCD (Hydroxypropyl-ß-cyclodextrin) may be employed in in vitro glucuronidation incubations up to 0.5% w/v without affecting the Cl(int) of 4-MU. Although NMP (N-methyl-2-pyrrolidone) and DMA (N,N-dimethylacetamide); showed low IC(75) values approximately 0.1% w/v each, neither excipients altered the Cl(int) of 4-MUG (4-methylumbelliferyl-ß-D-glucuronide) formation. Our studies point toward possible applications of pharmaceutical excipients to carry out in vitro glucuronidation of substrates with poor aqueous solubility, in order to estimate Cl(int) and subsequently scaled organ clearance values.


Assuntos
Excipientes/farmacologia , Glucuronídeos/metabolismo , Himecromona/análogos & derivados , Microssomos Hepáticos/metabolismo , Solubilidade , beta-Ciclodextrinas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Acetamidas/farmacologia , Glucuronosiltransferase/metabolismo , Humanos , Himecromona/metabolismo , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Pirrolidinonas/farmacologia
19.
J Med Chem ; 53(15): 5400-21, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20684591

RESUMO

A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.


Assuntos
Aminopiridinas/síntese química , Naftiridinas/síntese química , Proteína Quinase C/antagonistas & inibidores , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
J Med Chem ; 53(15): 5422-38, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20684592

RESUMO

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.


Assuntos
2,2'-Dipiridil/análogos & derivados , Aminopiridinas/síntese química , Naftiridinas/síntese química , Piperazinas/síntese química , Proteína Quinase C/antagonistas & inibidores , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/farmacologia , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA