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1.
J Med Chem ; 67(12): 9816-9841, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38857426

RESUMO

Clinical guidelines for COPD and asthma recommend inhaled ß-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and ß2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas Muscarínicos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/administração & dosagem , Animais , Humanos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Administração por Inalação , Ratos , Descoberta de Drogas , Relação Estrutura-Atividade , Masculino , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
2.
J Med Chem ; 66(16): 11476-11497, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37561958

RESUMO

Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92a is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10f was identified as a chemically stable, potent, and in vivo balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.


Assuntos
Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Anti-Inflamatórios/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
3.
Curr Med Chem ; 29(3): 526-590, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34525915

RESUMO

Pulmonary surfactant is a complex lipoprotein mixture secreted into the alveolar lumen by type 2 pneumocytes, which is composed by tens of different lipids (approximately 90% of its entire mass) and surfactant proteins (approximately 10% of the mass). It is crucially involved in maintaining lung homeostasis by reducing the values of alveolar liquid surface tension close to zero at end-expiration, thereby avoiding the alveolar collapse, and assembling a chemical and physical barrier against inhaled pathogens. A deficient amount of surfactant or its functional inactivation is directly linked to a wide range of lung pathologies, including the neonatal respiratory distress syndrome. This paper reviews the main biophysical concepts of surfactant activity and its inactivation mechanisms, and describes the past, present and future roles of surfactant replacement therapy, focusing on the exogenous surfactant preparations marketed worldwide and new formulations under development. The closing section describes the pulmonary surfactant in the context of drug delivery. Thanks to its peculiar composition, biocompatibility, and alveolar spreading capability, the surfactant may work not only as a shuttle to the branched anatomy of the lung for other drugs but also as a modulator for their release, leading to innovative therapeutic avenues for the treatment of several respiratory diseases.


Assuntos
Surfactantes Pulmonares , Síndrome do Desconforto Respiratório do Recém-Nascido , Materiais Biocompatíveis/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Recém-Nascido , Pulmão , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico
4.
J Med Chem ; 64(13): 9100-9119, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142835

RESUMO

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Cobaias , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Receptor Muscarínico M3/metabolismo , Relação Estrutura-Atividade
5.
Anal Chem ; 93(26): 9049-9055, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34159790

RESUMO

Physical forms of active pharmaceutical ingredients (APIs) play a crucial role in drug discovery since 85% of API molecules exhibit polymorphism and sometimes complicated phase behavior, often resulting in important differences in the respective biochemical and physical properties. Characterization and quantitation of the different forms are becoming more and more essential in the pharmaceutical industry: once these characteristics are known, it is easier to choose the best solid form for development, formulation, manufacturing, and storage. Time domain-nuclear magnetic resonance (TD-NMR) has recently been used to develop a quantitation protocol for solid mixtures, named qSRC, based on the linear combination of T1 saturation recovery curves (SRCs) collected on a bench-top instrument. Despite its potentials and ease of use, a limited number of application cases have been reported in the literature since its development and many aspects remain to be clarified for the technique to be adopted as a robust routinely industrial analytical tool. In the present work, the reliability of the qSRC approach has been studied by focusing on the role played by key experimental variables, including mixture composition, signal-to-noise ratio, and T1 differences. In silico simulations were carried out for a wide range of theoretical cases to predict the expected level of accuracy obtainable for a given sample-parameter acquisition set and to clearly define the range of applicability of the method. Results of the simulation are presented alongside a comparison with three real-case studies of commercially available APIs: piroxicam, naproxen sodium, and benzocaine.


Assuntos
Imageamento por Ressonância Magnética , Preparações Farmacêuticas , Simulação por Computador , Espectroscopia de Ressonância Magnética , Reprodutibilidade dos Testes
6.
J Med Chem ; 60(24): 10026-10046, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29200281

RESUMO

Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.


Assuntos
Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Relação Estrutura-Atividade , Administração por Inalação , Animais , Sítios de Ligação , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Humanos , Masculino , Inibidores da Fosfodiesterase 4/administração & dosagem , Eosinofilia Pulmonar/tratamento farmacológico , Pirrolidinas/química , Ratos Endogâmicos BN , Doenças Respiratórias/tratamento farmacológico , Tiazóis/química
7.
Pediatr Res ; 82(6): 1056-1063, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28723887

RESUMO

BackgroundThe intratracheal (IT) administration of budesonide using surfactant as a vehicle has been shown to reduce the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. The objective of this study was to characterize the in vitro characteristics and in vivo safety and efficacy of the extemporaneous combination of budesonide and poractant alfa.MethodsThe stability, minimum surface tension, and viscosity of the preparation were evaluated by means of high-performance liquid chromatography (HPLC), Wilhelmy balance, and Rheometer, respectively. The safety and efficacy of the IT administration of the mixture were tested in two respiratory distress syndrome (RDS) animal models: twenty-seventh day gestational age premature rabbits and surfactant-depleted adult rabbits.ResultsA pre-formulation trial identified a suitable procedure to ensure the homogeneity and stability of the formulation. Wilhelmy Balance tests clarified that budesonide supplementation has no detrimental effect on poractant alfa surface tension activity. The addition of budesonide to poractant alfa did not affect the physiological response to surfactant treatment in both RDS animal models, and was associated to a significant reduction of lung inflammation in surfactant-depleted rabbits.ConclusionOur in vitro and in vivo analysis suggests that the IT administration of a characterized extemporaneous combination of poractant alfa and budesonide is a safe and efficacious procedure in the context of RDS.


Assuntos
Produtos Biológicos/administração & dosagem , Broncodilatadores/administração & dosagem , Displasia Broncopulmonar/tratamento farmacológico , Budesonida/administração & dosagem , Fosfolipídeos/administração & dosagem , Surfactantes Pulmonares/administração & dosagem , Animais , Produtos Biológicos/efeitos adversos , Líquido da Lavagem Broncoalveolar , Broncodilatadores/efeitos adversos , Budesonida/efeitos adversos , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Feminino , Técnicas In Vitro , Fosfolipídeos/efeitos adversos , Gravidez , Coelhos , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Tensão Superficial , Traqueia , Viscosidade
8.
Medicine (Baltimore) ; 96(50): e9162, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29390325

RESUMO

Ambulatory blood pressure monitoring (ABPM) is a helpful tool to comprehensively identify and diagnose arterial hypertension. Moreover, it allows to better identify alterations in the circadian BP profile, as the nocturnal "nondipping" status, characterized by a lack of the physiological 10% night BP reduction and associated with a greater risk of target organ damage. However, ABPM has some limitations such as restricted availability, discomfort, particularly at night, cost implications, and reproducibility.Aim of the study was evaluate if the "nondipping" phenomenon may be related to low degree of tolerance to ABPM. Additionally, to determine whether self-reported events of sleep disorders and nighttime urinations may affect the "nondipping" status.From January 2013 to December 2015, we consecutively evaluated 1046 patients with arterial hypertension, performing ABPM, considering a tolerance index calculated on the basis of the patients' responses to a questionnaire.Thirty-eight out of 1046 patients showed complete lack of tolerance to the instrument during the day, whilst 126 during the night. There were no statistically significant differences in daytime and nighttime values of tolerance to the instrument between "dippers" and "nondippers," between "extreme-dippers" and the remaining patients or between "reverse-dippers" and the remaining patients. There were no statistically significant differences in the number of nocturnal awakenings between the groups. However, we found that the number of awakenings followed by urination was higher in "nondipping" patients and in "reverse-dipping" patients compared to the other groups.We found that the poor tolerance to the instrument does not seem to influence the BP "dipping" phenomenon among hypertensive individuals. Moreover, we think that in the evaluation of the ABPM data, factors, such as nocturnal urination and sleep disorders, need to be carefully taken into account, since may lead to a higher incidence of "nondipping" pattern.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Hipertensão/fisiopatologia , Aceitação pelo Paciente de Cuidados de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
9.
J Med Chem ; 57(3): 793-816, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24400806

RESUMO

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Asma/tratamento farmacológico , Benzoatos/síntese química , Pneumopatias Obstrutivas/tratamento farmacológico , Inibidores da Fosfodiesterase 4/síntese química , Sulfonamidas/síntese química , para-Aminobenzoatos/síntese química , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Linhagem Celular , Doença Crônica , Cristalografia por Raios X , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Eosinofilia/patologia , Ésteres , Cobaias , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Simulação de Acoplamento Molecular , Ovalbumina , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Conformação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , para-Aminobenzoatos/química , para-Aminobenzoatos/farmacologia
10.
Eur J Mass Spectrom (Chichester) ; 19(6): 475-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24378465

RESUMO

During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Derivados da Escopolamina/farmacocinética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Administração por Inalação , Aerossóis , Animais , Antagonistas Colinérgicos/farmacocinética , Vias de Administração de Medicamentos , Descoberta de Drogas , Cobaias , Masculino , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/metabolismo , Brometo de Tiotrópio , Distribuição Tecidual
11.
Am J Respir Cell Mol Biol ; 37(5): 617-23, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17600310

RESUMO

Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen species (ROS), have been proposed to be responsible for the inflammatory process of COPD. However, this issue remains unsettled. By gas chromatography/mass spectrometry (GC/MS) we show that acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes, are contained in aqueous cigarette smoke extract (CSE) at micromolar concentrations and mimic CSE in evoking the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-alpha from the human macrophagic cell line U937. In addition, acrolein (10-30 microM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30-100 microM), an endogenous alpha,beta-unsaturated aldehyde that is abundant in lungs of patients with COPD, stimulated the release of IL-8 from U937 cells, whereas the saturated aldehyde, acetaldehyde, was ineffective. CSE-evoked IL-8 release was remarkably (> 80%) inhibited by N-acetyl-cysteine (0.1-3 mM) or glutathione monoethyl ester (1-3 mM). Both compounds, by forming covalent adducts (Michael adducts), completely removed unsaturated aldehydes from CSE. Our data demonstrate that alpha,beta-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, and suggest that they might contribute to pulmonary inflammation associated with cigarette smoke.


Assuntos
Aldeídos/efeitos adversos , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Macrófagos/metabolismo , Fumar/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Células U937
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