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1.
Biomed Chromatogr ; 38(7): e5871, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38599686

RESUMO

We report the development and the validation of a sensitive liquid chromatography-mass spectrometry (LC-MS/MS) method for mometasone furoate (MF) analysis in human plasma. Plasma samples were processed through liquid-liquid extraction and analyzed using LC-MS/MS operating in positive mode using multiple reaction monitoring of transitions m/z 520.9 â†’ 355.0 and m/z 525.8 â†’ 355.0 for MF and the internal standard (IS), respectively. Separation was achieved at 1.0 mL/min on a C18 column using a gradient elution of mobile phase of 0.05% ammonia in water (phase A) and acetonitrile (phase B). The assay range was 0.250-100 pg/mL and proved to be accurate and precise MF. Normalized recoveries were consistent and reproducible with a coefficient of variation (CV%) value of 6.0. The CV (%) of the IS normalized matrix factor was not observed in normal, lipemic, and hemolyzed plasmas. Dilutions of 1:10 were accurately quantified. A cycle of three freeze and thaw and stabilities at room temperature and on the autosampler were demonstrated. In addition, MF in the presence of indacaterol and glycopyrronium was proven to be stable at -70°C for at least 157 days. The present method was successfully applied to quantify MF in patients receiving MF, indacaterol, and glycopyrronium as a fixed-dose combination.


Assuntos
Furoato de Mometasona , Espectrometria de Massas em Tandem , Humanos , Furoato de Mometasona/sangue , Furoato de Mometasona/farmacocinética , Furoato de Mometasona/química , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , Cromatografia Líquida/métodos , Modelos Lineares , Sensibilidade e Especificidade , Estabilidade de Medicamentos , Extração Líquido-Líquido/métodos , Limite de Detecção , Espectrometria de Massa com Cromatografia Líquida
2.
Eur Respir J ; 61(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36822634

RESUMO

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.


Assuntos
Asma , Hipersensibilidade Imediata , Humanos , Administração por Inalação , Alérgenos/efeitos adversos , Testes de Provocação Brônquica , Estudos Cross-Over , Citocinas , Método Duplo-Cego , Volume Expiratório Forçado , Fragmentos de Imunoglobulinas/uso terapêutico , Escarro , Linfopoietina do Estroma do Timo , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade
3.
Pulm Pharmacol Ther ; 70: 102068, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34329722

RESUMO

Once-daily (o.d.) fixed-dose combinations of mometasone furoate/indacaterol acetate (MF/IND) and mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY), both delivered via the Breezhaler® device, are approved for the maintenance treatment of asthma. Across these fixed-dose combinations, while the doses of bronchodilators remain the same, the nominal doses of mometasone furoate in micrograms differ. This article presents the steps followed in bridging the mometasone furoate doses at the corresponding dose strengths in the mometasone furoate formulation delivered via the Twisthaler® and mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulations delivered via the Breezhaler®. These were: (i) bridging the mometasone furoate doses in the Twisthaler® (previously approved) to mometasone furoate doses in the Breezhaler®; (ii) bridging the mometasone furoate doses in the Breezhaler® to mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation. Following this stepwise approach, it was determined that mometasone furoate 80 µg o.d. (medium-dose strength) and 160 µg o.d. (high-dose strength) in mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation provided comparable inhaled corticosteroid efficacy to mometasone furoate 160 µg o.d. (medium-dose strength) and 320 µg o.d. (high-dose strength) in the mometasone furoate/indacaterol acetate formulation, respectively. These doses were used in the PLATINUM Phase III clinical program that investigated the efficacy and safety of mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide combinations in patients with asthma.


Assuntos
Asma , Glicopirrolato , Administração por Inalação , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Glicopirrolato/uso terapêutico , Humanos , Indanos/uso terapêutico , Furoato de Mometasona , Quinolonas , Resultado do Tratamento
4.
Nat Chem Biol ; 12(11): 896-898, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27595330

RESUMO

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Imidazóis/farmacologia , Rim/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirrolidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sistema Cardiovascular/metabolismo , Humanos , Imidazóis/química , Rim/metabolismo , Testes de Função Renal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/química
5.
Nat Chem Biol ; 11(7): 511-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26030728

RESUMO

Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.


Assuntos
Processamento Alternativo , Atrofia Muscular Espinal/tratamento farmacológico , RNA de Cadeia Dupla/agonistas , Ribonucleoproteína Nuclear Pequena U1/agonistas , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Animais , Sítios de Ligação , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/mortalidade , Atrofia Muscular Espinal/patologia , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteólise , Precursores de RNA/agonistas , Precursores de RNA/química , Precursores de RNA/metabolismo , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/metabolismo , Ribonucleoproteína Nuclear Pequena U1/química , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Análise de Sobrevida , Proteína 2 de Sobrevivência do Neurônio Motor/química , Proteína 2 de Sobrevivência do Neurônio Motor/genética
7.
Bioorg Med Chem Lett ; 26(4): 1245-8, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26804232

RESUMO

Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diamida/química , Inibidores Enzimáticos/química , Animais , Linhagem Celular Tumoral , Diacilglicerol O-Aciltransferase/metabolismo , Diamida/síntese química , Diamida/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Clin Drug Investig ; 43(9): 719-728, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37682405

RESUMO

BACKGROUND: Indacaterol acetate (IND), a long-acting ß2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma. METHODS: In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment. RESULTS: In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 µg group and 25% patients in IND 150 µg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile. CONCLUSIONS: Once-daily IND 75 µg and IND 150 µg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 µg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02892019; 08-Sep-2016).


Assuntos
Asma , Humanos , Criança , Asma/diagnóstico , Asma/tratamento farmacológico , Método Duplo-Cego , Volume Expiratório Forçado , Acetatos
11.
Transl Vis Sci Technol ; 11(11): 15, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36394843

RESUMO

Purpose: This first-in-human (FIH) study evaluated the safety, tolerability, pharmacokinetics, and effect on corneal sensitivity of topical ocular SAF312 in healthy participants. Methods: This double-masked, randomized study comprised single-ascending dose (SAD), multiple-ascending dose (MAD), and esthesiometry parts. In SAD and MAD, 8 participants in each dose cohort were randomized 3:1 to receive SAF312 or vehicle, 1 drop once (SAD), or 1 drop 4 or 8 times daily for 7 days (MAD). Safety and pharmacokinetics were the primary and secondary objectives. Blink rate, tear production, tear film break-up time (TFBUT), and corneal sensitivity were also explored. Results: SAF312 was tolerated in single and multiple doses, including the maximum concentration of 2.5% dosed up to 1 drop 8 times daily for 7 days. Most adverse events (AEs) were mild and similar between SAF312 and vehicle-treated groups. No serious AEs were reported. SAF312 was rapidly absorbed, and had low systemic exposure. After supratherapeutic dosing for 7 days, mean steady-state exposures of SAF312 were low and afforded safety margins of >70-fold compared with no-observed-AE levels following oral dosing in preclinical studies. No clinically relevant changes were observed in blink rate, tear production, and TFBUT. SAF312 showed no undesired anesthetic effect on the cornea. Conclusions: SAF312 was well tolerated, with no ocular or systemic safety concerns; had no anesthetic effect, and demonstrated rapid topical absorption with low systemic exposure. Translational Relevance: This work bridges the gap between basic research and clinical care by providing FIH data of SAF312, supporting the further investigation as a potential treatment for ocular surface pain.


Assuntos
Córnea , Canais de Cátion TRPV , Humanos , Voluntários Saudáveis , Método Duplo-Cego
12.
J Clin Invest ; 118(9): 3109-22, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18677408

RESUMO

Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo- and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Benzamidas , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Mesilato de Imatinib , Camundongos , Modelos Biológicos , Neurônios/metabolismo , Oligopeptídeos/administração & dosagem , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem
13.
Bioorg Med Chem Lett ; 21(5): 1422-4, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21295471

RESUMO

A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites.


Assuntos
Anti-Helmínticos/farmacologia , Benzimidazóis/farmacologia , Inibidores do Citocromo P-450 CYP3A , Mutagênicos/farmacologia , Salmonella typhimurium/efeitos dos fármacos , Albendazol/farmacologia , Citocromo P-450 CYP3A , Testes de Mutagenicidade , Salmonella typhimurium/genética , Fatores de Tempo
14.
Eur J Drug Metab Pharmacokinet ; 46(4): 487-504, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34024035

RESUMO

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.


Assuntos
Asma/tratamento farmacológico , Glicopirrolato/análogos & derivados , Indanos/farmacocinética , Modelos Biológicos , Furoato de Mometasona/farmacocinética , Quinolonas/farmacocinética , Administração por Inalação , Adolescente , Adulto , Idoso , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacocinética , Criança , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Glicopirrolato/administração & dosagem , Glicopirrolato/farmacocinética , Humanos , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona/administração & dosagem , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
15.
J Med Chem ; 64(8): 4744-4761, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822618

RESUMO

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.


Assuntos
Desenho de Fármacos , Splicing de RNA , Tiadiazóis/química , Animais , Meia-Vida , Halogênios/química , Humanos , Masculino , Camundongos , Conformação Molecular , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Oxigênio/química , Piridazinas/química , Splicing de RNA/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Enxofre/química , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Tiadiazóis/metabolismo , Tiadiazóis/farmacologia
16.
J Med Chem ; 61(24): 11021-11036, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30407821

RESUMO

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.


Assuntos
Encéfalo/efeitos dos fármacos , Canal de Potássio ERG1/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Piridazinas/química , Administração Oral , Animais , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/antagonistas & inibidores , Humanos , Camundongos Endogâmicos C57BL , Neurônios Motores/efeitos dos fármacos , Atrofia Muscular Espinal/genética , Piridazinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Splicing de RNA , Ratos Sprague-Dawley , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética
17.
J Med Chem ; 60(16): 7099-7107, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28771350

RESUMO

The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Regulação Alostérica , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Células HEK293 , Humanos , Masculino , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Proteína Quinase 1 Deficiente de Lisina WNK
18.
J Med Chem ; 60(11): 4657-4664, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28498655

RESUMO

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Dieta Hiperlipídica , Inibidores Enzimáticos/farmacologia , Obesidade/fisiopatologia , Triglicerídeos/sangue , Aumento de Peso/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Animais , Cães , Método Duplo-Cego , Descoberta de Drogas , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Período Pós-Prandial , Ratos , Ratos Sprague-Dawley , Adulto Jovem
20.
J Med Chem ; 46(25): 5428-36, 2003 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-14640551

RESUMO

Several 1,2-benzisoxazole phosphorodiamidates have been designed as prodrugs of phosphoramide mustard requiring bioreductive activation. Enzymatic reduction of 1,2-benziosoxazole moiety is expected to result in the formation of imine intermediate due to the cleavage of the N-O bond. The imine should then be spontaneously hydrolyzed to a ketone metabolite, thereby facilitating base-catalyzed beta-elimination of cytotoxic phosphoramide mustard. As expected, the proposed prodrugs 4, 9, and 12 were at least 3-5-fold more potent cytotoxins than control compounds 5 and 15, which lack in the phosphoramide mustard group. Upon incubation with phenobarb-induced rat liver S-9 fraction, compounds 4, 9, and 12 underwent extensive NADPH-dependent metabolism with concomitant generation of alkylating activity under both hypoxic and oxic conditions. Corresponding ketone metabolites were detected for 9 and 15. NADPH-dependent bioreduction of 15 to its ketone metabolite 16 was located in the microsomal fraction and inhibited by SKF-525A and pCMBA. Compared with phenobarb-induced rat liver microsomal fraction, incubation of 15 with rat or human p450 reductase microsomes showed moderate generation of 16. Microsomal cytochrome p450 and/or p450 reductase appear to be involved in the reductive metabolism of 1,2-benzisoxazole moiety under hypoxic as well as oxic conditions.


Assuntos
Antineoplásicos Alquilantes/síntese química , Isoxazóis/síntese química , Mostardas de Fosforamida/metabolismo , Pró-Fármacos/síntese química , Animais , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Técnicas In Vitro , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , NADP/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Oxirredução , Mostardas de Fosforamida/administração & dosagem , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ratos , Relação Estrutura-Atividade
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