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1.
Bioorg Med Chem Lett ; 21(24): 7281-6, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22047692

RESUMO

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.


Assuntos
Inibidores Enzimáticos/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Ácidos Nicotínicos/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacologia , Ratos , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual
2.
Bioorg Med Chem Lett ; 20(22): 6387-93, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20933411

RESUMO

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Ciclopropanos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Ciclopropanos/química , Ciclopropanos/uso terapêutico , Cães , Feminino , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Humanos , Macaca mulatta , Masculino , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 19(17): 5266-9, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19640717

RESUMO

Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.


Assuntos
Anti-Inflamatórios/química , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/química , Quinolinas/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Citocromo P-450 CYP2C9 , Cobaias , Humanos , Leucócitos Mononucleares/metabolismo , Ovalbumina/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Saimiri , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 18(20): 5554-8, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18835163

RESUMO

A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-alpha in human whole blood and minimizing affinity for the hERG potassium channel. From these studies, compounds 18 and 20 (MK-0873) were identified as optimized PDE4 inhibitors with good overall in vitro and in vivo profiles and selected as development candidates.


Assuntos
Química Farmacêutica/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Naftiridinas/síntese química , Animais , Cães , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/química , Modelos Químicos , Naftiridinas/farmacologia , Ligação Proteica , Ratos , Saimiri , Fator de Necrose Tumoral alfa/metabolismo
5.
Bioorg Med Chem Lett ; 18(4): 1407-12, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18207397

RESUMO

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Desenho de Fármacos , Cobaias , Humanos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade
6.
J Med Chem ; 46(12): 2413-26, 2003 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12773045

RESUMO

A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Álcoois/síntese química , Óxidos N-Cíclicos/síntese química , Inibidores de Fosfodiesterase/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Piridinas/síntese química , Álcoois/farmacocinética , Álcoois/farmacologia , Álcoois/toxicidade , Animais , Broncoconstrição/efeitos dos fármacos , Cristalografia por Raios X , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Cobaias , Humanos , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/toxicidade , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/toxicidade , Ratos , Saimiri , Ovinos , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamente
7.
J Med Chem ; 54(14): 5082-96, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21661758

RESUMO

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.


Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fígado/enzimologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tetrazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Linhagem Celular , Difusão , Cães , Feminino , Glândula de Harder/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Técnicas In Vitro , Transportador 1 de Ânion Orgânico Específico do Fígado , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Especificidade da Espécie , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia , Distribuição Tecidual
8.
J Biomol Screen ; 15(2): 169-76, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20086206

RESUMO

A multiplexed cell assay has been optimized to measure the activities of fatty acyl-CoA elongase, delta-5 desaturase (Delta5D), delta-6 desaturase (Delta6D), and delta-9 desaturase (Delta9D) together using (14)C-labeled tracers in HepG2 cells, which express the human stearoyl-CoA desaturase-1 isoform (SCD1) exclusively. The Delta5 and Delta9 desaturase activities are indexed by the efficient conversion of [1-(14)C]-eicosatrienoic acid (C20:3, cis-8,11,14) to (14)C-arachidonic acid (C20:4, cis-5,8,11,14) and the conversion of [1-(14)C]-stearic acid to (14)C-oleic acid (C18:1, cis-9), respectively. CP-74006 potently blocks the Delta5D activity with an IC(50) value of 20 nM and simplifies the metabolism of [1-(14)C]-alpha-linolenate (C18:3, cis-9,12,15) by accumulating (14)C-eicosatetraenoic acid (C20:4, cis-8,11,14,17) as the major (14)C-eicosatrienoic acid (C20:3, cis-11,14,17) and (14)C-docosatetraenoic acid (C22:4, cis-10,13,16,19) as the minor metabolites through Delta6 desaturation and elongation. This simplified metabolite spectrum enables the delineation of the Delta6D activity by comparing the combined Delta6D/elongase activity index of the (14)C-(C20:4/C18:3) ratio with the corresponding elongation index of the (14)C-(C20:3/C18:3) ratio following compound treatment. SC-26196 and sterculic acid specifically inhibit the Delta6D and Delta9D activities with an IC(50) value of 0.1 microM and 0.9 microM, respectively. This medium-throughput cell assay provides an efficient tool in the identification of specific desaturase and elongase inhibitors.


Assuntos
Acetiltransferases/antagonistas & inibidores , Acil Coenzima A/antagonistas & inibidores , Bioensaio , Ácidos Graxos Dessaturases/antagonistas & inibidores , Linoleoil-CoA Desaturase/antagonistas & inibidores , Acetiltransferases/química , Acetiltransferases/metabolismo , Acil Coenzima A/química , Acil Coenzima A/metabolismo , Radioisótopos de Carbono , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/química , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Cinética , Linoleoil-CoA Desaturase/química , Linoleoil-CoA Desaturase/metabolismo , Modelos Biológicos , Modelos Químicos
9.
ACS Med Chem Lett ; 1(4): 170-4, 2010 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900191

RESUMO

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

10.
Bioorg Med Chem Lett ; 16(10): 2608-12, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16516471

RESUMO

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.


Assuntos
Nitrogênio/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/farmacocinética , Ratos , Saimiri
11.
Bioorg Med Chem Lett ; 15(23): 5241-6, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16168647

RESUMO

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cobaias , Humanos , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/toxicidade , Quinolinas/toxicidade , Ratos , Saimiri , Ovinos , Relação Estrutura-Atividade , Vômito/induzido quimicamente
12.
Bioorg Med Chem Lett ; 14(5): 1201-3, 2004 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-14980665

RESUMO

Loxoprofen, its trans-alcohol and cis-alcohol metabolites were evaluated for selectivity of inhibition of COX-2 over COX-1. The (2S,1'R,2'S)-trans-alcohol derivative was found to be the most active metabolite and to be a potent and nonselective inhibitor of COX-2 and COX-1 in both enzyme and human whole blood assays.


Assuntos
Inibidores de Ciclo-Oxigenase/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/antagonistas & inibidores , Fenilpropionatos/metabolismo , Fenilpropionatos/farmacologia , Álcoois/metabolismo , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/química , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoenzimas/metabolismo , Proteínas de Membrana , Fenilpropionatos/química , Prostaglandina-Endoperóxido Sintases/metabolismo
13.
Bioorg Med Chem Lett ; 13(4): 741-4, 2003 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-12639571

RESUMO

The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv).


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Aminopiridinas/farmacocinética , Animais , Broncoconstrição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Furões , Cobaias , Meia-Vida , Humanos , Concentração Inibidora 50 , Ratos , Ovinos , Relação Estrutura-Atividade , Equivalência Terapêutica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vômito/induzido quimicamente
14.
Bioorg Med Chem Lett ; 13(11): 1923-6, 2003 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-12749899

RESUMO

The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Picolinas/química , Picolinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Meia-Vida , Humanos , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Picolinas/síntese química , Picolinas/farmacocinética , Ratos , Saimiri , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
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