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1.
Brain Behav Immun ; 74: 265-276, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30218783

RESUMO

Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1ß (IL-1ß) injections. We initiated GSK247246 treatment (i.p at 7 mg/kg or 20 mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.


Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Substância Branca/lesões , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encefalopatias/tratamento farmacológico , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos , Microglia/metabolismo , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Neurogênese , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligodendroglia , Gravidez , Nascimento Prematuro/tratamento farmacológico , Receptores Histamínicos/metabolismo , Substância Branca/metabolismo
2.
Bioorg Med Chem Lett ; 24(4): 1098-103, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24462665

RESUMO

Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 µM) and partial PPARγ agonist (EC50=0.25 µM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).


Assuntos
Angiotensina II/metabolismo , Descoberta de Drogas , Indazóis/farmacologia , PPAR gama/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Indazóis/síntese química , Indazóis/química , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
3.
J Invest Dermatol ; 141(9): 2272-2279, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33744298

RESUMO

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.


Assuntos
Anti-Inflamatórios/uso terapêutico , Compostos de Boro/uso terapêutico , Inflamação/tratamento farmacológico , Calicreínas/antagonistas & inibidores , Síndrome de Netherton/tratamento farmacológico , Pele/patologia , Administração Tópica , Animais , Modelos Animais de Doenças , Humanos , Calicreínas/genética , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Pele/efeitos dos fármacos , Creme para a Pele
5.
J Med Chem ; 62(10): 5096-5110, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013427

RESUMO

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Disponibilidade Biológica , Linhagem Celular , Doença Crônica , Desenho de Fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Esclerose Múltipla/tratamento farmacológico , Pirazóis/farmacocinética , Ratos , Retinose Pigmentar/tratamento farmacológico , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 18(23): 6251-4, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18947994

RESUMO

We report the design and synthesis of equipotent PPARalpha/gamma dual agonists starting from selective PPAR alpha agonist 1. In vivo data for 7 in the Zucker fa/fa rat are presented.


Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Pirazóis/síntese química , Animais , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Isoformas de Proteínas , Pirazóis/química , Pirazóis/toxicidade , Ratos , Ratos Zucker , Relação Estrutura-Atividade
7.
J Med Chem ; 50(4): 685-95, 2007 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-17243659

RESUMO

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.


Assuntos
HDL-Colesterol/sangue , PPAR alfa/agonistas , Propionatos/síntese química , Tiazóis/síntese química , Animais , Apolipoproteína A-I/genética , VLDL-Colesterol/sangue , Cristalografia por Raios X , Cães , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , PPAR alfa/química , Propionatos/farmacocinética , Propionatos/farmacologia , Estrutura Terciária de Proteína , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triglicerídeos/sangue
8.
J Med Chem ; 59(23): 10738-10749, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27933945

RESUMO

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.


Assuntos
Inibidores Enzimáticos/farmacologia , Lactamas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Distribuição Tecidual
9.
Nat Med ; 22(2): 202-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26752518

RESUMO

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.


Assuntos
Benzoxazóis/farmacologia , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Insuficiência de Múltiplos Órgãos/genética , Oxazolidinonas/farmacologia , Pancreatite/genética , Propionatos/farmacologia , RNA Mensageiro/metabolismo , Doença Aguda , Animais , Cromatografia Líquida , Cristalografia por Raios X , Modelos Animais de Doenças , Células HEK293 , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Rim/metabolismo , Rim/patologia , Quinurenina 3-Mono-Oxigenase/genética , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Knockout , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/complicações , Pancreatite/patologia , Ratos , Espectrometria de Massas em Tandem , Triptofano/metabolismo
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