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1.
Biol Pharm Bull ; 44(2): 188-196, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518672

RESUMO

ONO-4641, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid (ceralifimod), is a second-generation sphingosine 1-phosphate receptor agonist selective for sphingosine 1-phosphate receptors 1 and 5, and has clinical effects in multiple sclerosis. The objective of the present study was to explore other potential indications for ONO-4641 based on its immunomodulatory effects. ONO-4641 was tested in non-obese diabetic (NOD) mice, an animal model of spontaneous type 1 diabetes mellitus, an autoimmune disease with unmet medical needs. ONO-4641 at a dose of 0.1 mg/kg prevented the onset of diabetes mellitus in NOD mice. Furthermore, ONO-4641 at doses of 0.03 and 0.1 mg/kg decreased diabetic prevalence in NOD mice after the onset of diabetes mellitus in a dose-dependent manner. Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus.


Assuntos
Azetidinas/farmacologia , Diabetes Mellitus Tipo 1/prevenção & controle , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Animais , Azetidinas/uso terapêutico , Glicemia/análise , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Naftalenos/uso terapêutico
2.
ACS Med Chem Lett ; 8(12): 1281-1286, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259748

RESUMO

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

3.
J Med Chem ; 60(23): 9508-9530, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29120624

RESUMO

The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).


Assuntos
Azetidinas/farmacologia , Linfócitos/efeitos dos fármacos , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Doenças Autoimunes/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/química , Azetidinas/farmacocinética , Células CHO , Cricetulus , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacocinética , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
4.
Artigo em Inglês | MEDLINE | ID: mdl-28410666

RESUMO

Although the effectiveness of CysLT1 receptor antagonists on asthma has been clinically established, the effects of CysLT2 receptor antagonists are still unclear. The purpose of this study was to develop a new CysLT1 and CysLT2 receptors-mediated anaphylaxis guinea pig model using S-hexyl GSH, a γ-glutamyl transpeptidase (GTP) inhibitor, to suppress conversion of LTC4 to LTD4. Actively sensitized guinea pigs were challenged with OVA in the absence or presence of S-hexyl GSH, and survival rate following anaphylactic response was monitored. OVA-induced fatal anaphylaxis in the absence of S-hexyl GSH was almost completely inhibited by montelukast, a CysLT1 receptor antagonist, but not by the CysLT2 receptor antagonist BayCysLT2RA. However, under treatment with S-hexyl-GSH, the inhibitory effect of motelukast was dramatically diminished, whereas that of BayCysLT2RA was markedly increased. The dual CysLT1/2 receptor antagonist ONO-6950 effectively inhibited anaphylactic response in both S-hexyl GSH-treated and non-treated animals. LC/MS/MS analysis revealed that S-hexyl GSH treatment actually inhibited LTC4 metabolism in the blood and lung tissues. Using S-hexyl GSH, we developed a novel CysLT1 and CysLT2 receptors-mediated anaphylaxis guinea pig model that can be useful for not only screening both CysLT2 and CysLT1/2 receptors antagonists, but also for functional analysis of CysLT2 receptors.


Assuntos
Anafilaxia/tratamento farmacológico , Butiratos/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Indóis/administração & dosagem , Antagonistas de Leucotrienos/administração & dosagem , Ácidos Ftálicos/administração & dosagem , Receptores de Leucotrienos/metabolismo , Anafilaxia/induzido quimicamente , Anafilaxia/metabolismo , Animais , Butiratos/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Glutationa/efeitos adversos , Glutationa/análogos & derivados , Cobaias , Indóis/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Leucotrieno C4/sangue , Leucotrieno C4/metabolismo , Leucotrieno D4/sangue , Leucotrieno D4/metabolismo , Masculino , Ovalbumina/efeitos adversos , Ácidos Ftálicos/uso terapêutico , Análise de Sobrevida
5.
ACS Med Chem Lett ; 7(10): 913-918, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774128

RESUMO

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy.

6.
Eur J Pharmacol ; 765: 242-8, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26318198

RESUMO

We assessed in this study the anti-asthmatic effects of ONO-6950, a novel cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors dual antagonist, in normal and S-hexyl glutathione (S-hexyl GSH)-treated guinea pigs, and compared these effects to those of montelukast, a CysLT1 selective receptor antagonist. Treatment with S-hexyl GSH reduced animals LTC4 metabolism, allowing practical evaluation of CysLT2 receptor-mediated airway response. ONO-6950 antagonized intracellular calcium signaling via human and guinea pig CysLT1 and CysLT2 receptors with IC50 values of 1.7 and 25 nM, respectively (human receptors) and 6.3 and 8.2 nM, respectively (guinea pig receptors). In normal guinea pigs, both ONO-6950 (1 or 0.3 mg/kg, p.o.) and the CysLT1 receptor antagonist montelukast (0.3 or 0.1 mg/kg, p.o.) fully attenuated CysLT1-mediated bronchoconstriction and airway vascular hyperpermeability induced by LTD4. On the other hand, in S-hexyl GSH-treated guinea pigs ONO-6950 at 3 mg/kg, p.o. or more almost completely inhibited bronchoconstriction and airway vascular hyperpermeability elicited by LTC4, while montelukast showed only partial or negligible inhibition of these airway responses. In ovalbumin sensitized guinea pigs, treatment with S-hexyl GSH on top of pyrilamine and indomethacin rendered antigen-induced bronchoconstriction sensitive to both CysLT1 and CysLT2 receptor antagonists. ONO-6950 strongly inhibited this asthmatic response to the level attained by combination therapy with montelukast and BayCysLT2RA, a selective CysLT2 receptor antagonist. These results clearly demonstrate that ONO-6950 is an orally active dual CysLT1/LT2 receptor antagonist that may provide a novel therapeutic option for patients with asthma.


Assuntos
Asma/tratamento farmacológico , Butiratos/uso terapêutico , Indóis/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Receptores de Leucotrienos/metabolismo , Administração Oral , Animais , Asma/imunologia , Butiratos/administração & dosagem , Células CHO , Cálcio/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Indóis/administração & dosagem , Antagonistas de Leucotrienos/administração & dosagem , Masculino , Estrutura Molecular , Receptores de Leucotrienos/genética , Sistema Respiratório/irrigação sanguínea , Sistema Respiratório/efeitos dos fármacos
7.
Cell ; 161(7): 1633-43, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26091040

RESUMO

Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with at least six cognate G protein-coupled receptors. Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease.


Assuntos
Cristalografia por Raios X , Sítios de Ligação , Cromatografia em Gel , Humanos , Ligantes , Modelos Moleculares , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/química , Bibliotecas de Moléculas Pequenas
8.
PLoS One ; 9(4): e93230, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24747415

RESUMO

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4-19 nM for recombinant autotaxin/ENPP2 proteins and 4.7-11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.


Assuntos
Carbolinas/farmacologia , Inibidores Enzimáticos/farmacologia , Lisofosfolipídeos/biossíntese , Lisofosfolipídeos/sangue , Diester Fosfórico Hidrolases/metabolismo , Uretra/efeitos dos fármacos , Uretra/fisiologia , Animais , Carbolinas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Relaxamento Muscular/efeitos dos fármacos , Pressão , Ratos , Fatores de Tempo
9.
Dysphagia ; 29(1): 61-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23907747

RESUMO

Patients who have an ischemic stroke are at high risk of swallowing disorders. Aspiration due to swallowing disorders, specifically delayed trigger of the pharyngeal stage of swallowing, predisposes such patients to pneumonia. In the present study, we evaluated swallowing reflex in a rat model of transient middle cerebral artery occlusion (tMCAO), which is one of the most common experimental animal models of cerebral ischemia, in order to develop a novel animal model of dysphagia following ischemic stroke. A swallowing reflex was elicited by a 10-s infusion of distilled water (DW) to the pharyngolaryngeal region in the tMCAO rat model. Swallowing reflex was estimated using the electromyographic activity of the mylohyoid muscle from 1 to 3 weeks after surgery. Two weeks after tMCAO, the number of swallows significantly decreased and the onset latency of the first swallow was prolonged compared with that of the sham group. The number of swallows in rats significantly increased by infusions of 10 mM citric acid and 0.6 µM capsaicin to the pharyngolaryngeal region compared with the number from infusion of DW. It has been reported that sensory stimulation of the pharyngolaryngeal region with citric acid, capsaicin, and L-menthol ameliorates hypofunction of pharyngeal-stage swallowing in dysphagia patients. Therefore, the tMCAO rat model may show some of the symptoms of pharyngeal-stage swallowing disorders, similar to those in patients with ischemic stroke. This rat tMCAO model has the potential to become a novel animal model of dysphagia following stroke that is useful for development of therapeutic methods and drugs.


Assuntos
Transtornos de Deglutição/etiologia , Deglutição/fisiologia , Faringe/fisiologia , Reflexo/fisiologia , Acidente Vascular Cerebral/complicações , Animais , Transtornos de Deglutição/fisiopatologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/fisiopatologia
10.
Bioorg Med Chem Lett ; 22(1): 144-8, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22153936

RESUMO

Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice.


Assuntos
Química Farmacêutica/métodos , Lisofosfolipídeos/antagonistas & inibidores , Naftalenos/química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingosina/análogos & derivados , Administração Oral , Animais , Benzeno/química , Cloro/química , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Modelos Químicos , Ratos , Esfingosina/antagonistas & inibidores , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 21(13): 3885-9, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21641216

RESUMO

Structure-activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P(1) receptor agonist with high selectivity against S1P(3) and enhanced efficacy in lowering peripheral lymphocyte counts in mice.


Assuntos
Naftalenos/síntese química , Propanóis/química , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cloridrato de Fingolimode , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Naftalenos/administração & dosagem , Naftalenos/farmacologia , Propanóis/administração & dosagem , Propanóis/farmacologia , Propilenoglicóis , Esfingosina/análogos & derivados , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 21(5): 1390-3, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21295477

RESUMO

Structure-activity relationship of sphingosine-1-phosphate receptor agonist was examined. In terms of reducing the flexibility of molecule, hit compound 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Novel S1P agonists with cinnamyl scaffold or 1,2,5,6-tetrahydropyridine scaffold were identified.


Assuntos
Cinamatos/síntese química , Receptores de Lisoesfingolipídeo/agonistas , beta-Alanina/síntese química , Animais , Cinamatos/química , Cloridrato de Fingolimode , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Ratos , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-Atividade , beta-Alanina/química
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