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1.
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.

2.
Biochem Biophys Rep ; 10: 82-87, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28955738

RESUMO

Basophils have been erroneously considered as minor relatives of mast cells, due to some phenotypic similarity between them. While recent studies have revealed non-redundant roles for basophils in various immune responses, basophil-derived effector molecules, including lipid mediators, remain poorly characterized, compared to mast cell-derived ones. Here we analyzed and compared eicosanoids produced by mouse basophils and mast cells when stimulated with IgE plus allergens. The production of 5-LOX metabolites such as LTB4 and 5-HETE was detected as early as 0.5 h post-stimulation in both cell types, even though their amounts were much smaller in basophils than in mast cells. In contrast, basophils and mast cells showed distinct time course in the production of COX metabolites, including PGD2, PGE2 and 11-HETE. Their production by mast cells was detected at both 0.5 and 6 h post-stimulation while that by basophils was detectable only at 6 h. Of note, mast cells showed 8-9 times higher levels of COX-1 than did basophils at the resting status. In contrast to unaltered COX-1 expression with or without stimulation, COX-2 expression was up-regulated in both cell types upon activation. Importantly, when activated, basophils expressed 4-5 times higher levels of COX-2 than did mast cells. In accordance with these findings, the late-phase production of the COX metabolites by basophils was completely ablated by COX-2 inhibitor whereas the early-phase production by mast cells was blocked by COX-1 but not COX-2 inhibitor. Thus, the production of COX metabolites is differentially regulated by COX-1 and COX-2 in basophils and mast cells.

3.
J Cachexia Sarcopenia Muscle ; 5(4): 329-37, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25267366

RESUMO

BACKGROUND: Anamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM. METHODS: Fluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response. RESULTS: ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs. CONCLUSION: ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

4.
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
5.
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
6.
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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