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1.
J Pharmacol Exp Ther ; 371(1): 208-218, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31375639

RESUMO

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORγt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORγt+ cells, and inhibition of RORγt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Interleucina-23/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Piperidinas/farmacologia , Psoríase/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Células COS , Células Cultivadas , Chlorocebus aethiops , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Piperidinas/uso terapêutico
2.
Bioorg Med Chem Lett ; 29(14): 1799-1806, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31101472

RESUMO

A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.


Assuntos
Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Quinolinas/química , Animais , Modelos Animais de Doenças , Humanos , Camundongos
3.
Ann Rheum Dis ; 76(11): 1931-1940, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28801346

RESUMO

OBJECTIVE: To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). METHODS: IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. RESULTS: IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-ß and fibroblast proliferation mediated by PDGF. CONCLUSION: We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements.


Assuntos
Benzotiazóis/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Bleomicina , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Antígeno 2 Relacionado a Fos , Hipertensão Pulmonar/etiologia , Camundongos , Camundongos Transgênicos , Miofibroblastos/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/complicações , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/agonistas , Fator de Crescimento Transformador beta/fisiologia , Resultado do Tratamento , Remodelação Vascular/efeitos dos fármacos
4.
Ann Rheum Dis ; 75(12): 2175-2183, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26961294

RESUMO

BACKGROUND: The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets. OBJECTIVE: To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis. METHODS: The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. RESULTS: Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3-intracellular effector of transforming growth factor (TGF)-ß1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-ß signalling pathways. CONCLUSIONS: These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.


Assuntos
Anti-Inflamatórios/farmacologia , Benzotiazóis/farmacologia , Fármacos Dermatológicos/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Sulfonamidas/farmacologia , Animais , Bleomicina , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Fibrose , Humanos , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Escleroderma Sistêmico/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização/efeitos dos fármacos
5.
Nat Commun ; 13(1): 3739, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768432

RESUMO

Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an "epigenetic checkpoint" for tumor immunity.


Assuntos
Linfócitos T CD8-Positivos , Melanoma , Metiltransferases , Receptor de Morte Celular Programada 1 , Proteínas Repressoras , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/genética , Melanoma/imunologia , Melanoma/terapia , Metiltransferases/antagonistas & inibidores , Metiltransferases/genética , Metiltransferases/imunologia , Metiltransferases/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
6.
PLoS One ; 15(5): e0233032, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413051

RESUMO

Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy-ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the ß-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 µM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving µM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.


Assuntos
Glicosaminoglicanos/metabolismo , Glicosídeos/uso terapêutico , Mucopolissacaridose VI/tratamento farmacológico , Mucopolissacaridose VI/metabolismo , Administração Oral , Animais , Bovinos , Células Cultivadas , Sulfatos de Condroitina , Dermatan Sulfato/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Glicosídeos/administração & dosagem , Glicosídeos/farmacocinética , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mucopolissacaridose VI/genética , Ratos , Ratos Sprague-Dawley
7.
J Med Chem ; 61(6): 2246-2265, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29446942

RESUMO

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.


Assuntos
Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Fibrose/prevenção & controle , Indóis/síntese química , Indóis/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Benzotiazóis/farmacocinética , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Linhagem Celular , Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
9.
Hepatol Commun ; 1(6): 524-537, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-29404476

RESUMO

IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet; the foz/foz model; the CCl4-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of ß-oxidation-related and fatty acid desaturation-related genes in both the methionine- and choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524-537).

10.
Biochem Pharmacol ; 66(7): 1171-80, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14505796

RESUMO

CXC-chemokine receptors 1 and 2 and their ligands (CXCL1, 2, 3, 5, 6, 7, and 8) induce the selective recruitment of neutrophils during inflammation. Such receptors have not been characterized yet in guinea pig, an animal inflammation model of interest. We report the identification, cloning, and characterization of a CXCL8 receptor in guinea pig. Human CXCL8 produced in vivo neutrophilia, chemotaxis and intracellular calcium release of guinea pig neutrophils. The expression of this receptor at their neutrophil surface was investigated. The cDNA encoding a functional CXCL8 receptor was cloned from guinea pig neutrophils and sequenced. It was synthesized using RT-PCR, with oligonucleotide primers derived from well conserved regions of published CXCL8 receptors. This sequence presented an open reading frame coding for 352 amino acids and shares, at the amino acid level, 70 and 69% identity with human and rabbit CXCR2, respectively. The receptor was mainly expressed in neutrophils but it was also present in kidney, lung, spleen and, to a less extent, in heart. Cloned receptor transfected cells showed that this receptor displayed high affinity for human CXCL8, slightly lower than the affinity observed with guinea pig neutrophils. CXC chemokines from both rabbit and human were shown to induce inositol phosphate accumulation in these transfected cells. Receptor binding and activation characteristics together with sequence homology suggested that we identified a guinea pig equivalent of the human CXCR2 receptor.


Assuntos
Interleucina-8/metabolismo , Receptores de Interleucina-8A/genética , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Quimiotaxia/fisiologia , Clonagem Molecular , Cobaias , Humanos , Fosfatos de Inositol/metabolismo , Dados de Sequência Molecular , Neutrófilos/fisiologia , Receptores de Interleucina-8A/isolamento & purificação , Receptores de Interleucina-8B/metabolismo , Homologia de Sequência de Aminoácidos
11.
J Med Chem ; 55(6): 2574-84, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22369198

RESUMO

The bradykinin (BK) B1 receptor is an attractive target for the treatment of chronic pain and inflammation. Starting from a dual B1 and B2 antagonist, novel antagonists were designed that display low-nanomolar affinity for human B1 receptor and selectivity over B2. Initially, potent imidazoline derivatives were studied, but these compounds suffered from low bioavailability. This issue could be overcome by the use of less basic amino derivatives leading to orally active compounds.


Assuntos
Analgésicos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Piperazinas/síntese química , Piperidinas/síntese química , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Humanos , Hiperalgesia/tratamento farmacológico , Imidazolinas/síntese química , Imidazolinas/farmacocinética , Imidazolinas/farmacologia , Masculino , Camundongos , Medição da Dor , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
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