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1.
J Pharmacol Exp Ther ; 333(2): 445-53, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20164299

RESUMO

Antagonists of the cannabinoid receptor 1 (CB1) impart anti-inflammatory activity even though, paradoxically, CB2 receptors are more predominant on cells of the immune system. We attempted to understand the mechanism of this activity by using an acute model of lipopolysaccharide-induced inflammation/stress in both rat and mouse, with selective antagonists to CB1 receptors. We demonstrate that the ability of a CB1 antagonist to inhibit release of proinflammatory cytokines is not dependent on either adrenal-derived catecholamines or corticosteroids or input from the pituitary or thymus glands but does involve the spleen. Furthermore, we show that the anti-inflammatory activity is retained without communication from the central nervous system following ganglionic blockade, suggesting a peripheral site of action. Finally, we show that the anti-inflammatory activity can be inhibited with the use of a selective beta2-adrenoceptor antagonist.


Assuntos
Anti-Inflamatórios/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores Adrenérgicos beta 2/fisiologia , Adrenalectomia , Antagonistas de Receptores Adrenérgicos beta 2 , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Artrite/fisiopatologia , Benzoxazinas/farmacologia , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Morfolinas/farmacologia , Naftalenos/farmacologia , Ratos , Ratos Endogâmicos Lew , Receptor CB1 de Canabinoide/fisiologia , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese
2.
Bioorg Med Chem Lett ; 20(4): 1388-94, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20097563

RESUMO

Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.


Assuntos
Fibrinolíticos/farmacologia , Ácido Glutâmico/síntese química , Piperidinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Fibrinolíticos/síntese química , Fibrinolíticos/química , Ácido Glutâmico/química , Ácido Glutâmico/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Ratos , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 19(21): 6148-56, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19796941

RESUMO

Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.


Assuntos
Fibrinolíticos/química , Ácido Glutâmico/química , Piperidinas/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Pirimidinas/química , Animais , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Humanos , Masculino , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 19(16): 4657-63, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19604694

RESUMO

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.


Assuntos
Ácido Glutâmico/química , Piperazinas/química , Inibidores da Agregação Plaquetária/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/química , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
6.
J Med Chem ; 53(5): 2010-37, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20141147

RESUMO

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.


Assuntos
Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2 , Piridinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Feminino , Glutamatos/síntese química , Glutamatos/farmacocinética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Piperazinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Piridinas/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade , Adulto Jovem
7.
J Pharmacol Exp Ther ; 314(3): 1248-56, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15980060

RESUMO

The purpose of this study is to demonstrate that sumanirole is a novel dopamine receptor agonist with high in vitro and in vivo selectivity for the D(2) receptor subtype. Sumanirole, (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Z)-2-butenedioate (1:1), is unique; it has greater than 200-fold selectivity for the D(2) receptor subtype versus the other dopamine receptor subtypes in radioligand binding assays. In cell-based assays, sumanirole is a fully efficacious agonist, with EC(50) values between 17 and 75 nM. In animals, sumanirole elicits many physiological responses attributed to D(2)-like receptor function. In rats, sumanirole is a full agonist for elevation of striatal acetylcholine levels (ED(50) = 12.1 micromol/kg i.p.). Sumanirole s.c. dose dependently decreased plasma prolactin levels and depressed dopamine neuron firing rates in the substantia nigra pars compacta with an ED(50) of 2.3 micromol/kg i.v. This high selectivity for D(2) receptors translates into excellent locomotor stimulant activity in animal models of Parkinson's disease. In reserpinized, alpha-methyl-para-tyrosine-treated rats, sumanirole caused a significant and sustained increase in horizontal activity at doses > or =12.5 micromol/kg s.c. In unilateral 6-hydroxydopamine-lesioned rats, sumanirole caused profound, sustained rotational behavior and was substantially more efficacious than any other agonist tested. Sumanirole-stimulated rotational behavior was blocked by the dopamine receptor antagonist haloperidol. Sumanirole dose dependently improved disability scores and locomotor activities of two of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In summary, sumanirole is the first published selective D(2) receptor agonist. The compound has activity in animal models of dopamine hypofunction and has a high level of efficacy in animal models of Parkinson's disease.


Assuntos
Benzimidazóis/farmacologia , Agonistas de Dopamina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Receptores de Dopamina D2/agonistas , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Intoxicação por MPTP/tratamento farmacológico , Macaca fascicularis , Masculino , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/psicologia , Ratos , Ratos Long-Evans
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