RESUMO
As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Sulfonamidas/síntese química , Tiazóis/síntese química , Administração Oral , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Disponibilidade Biológica , Células CHO , Clonagem Molecular , Cricetinae , Cães , Glicerol/sangue , Humanos , Macaca mulatta , Masculino , Ensaio Radioligante , Ratos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
A method is described for the evaluation of drug concentrations in plasma and brain from treated rats. The analyte is recovered from plasma or brain homogenate by liquid-liquid extraction and subsequently analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). A simple experimental protocol renders the procedure valuable for obtaining information rapidly on brain penetration and plasma exposure of specific classes of compounds. This methodology has been applied to evaluate brain penetration with 30 different compounds from the same discovery program. In an attempt to increase throughput in our screening efforts, mixture dosing was evaluated. Results from single compound administration were compared with results following administration of a mixture of four compounds. Preliminary results, with specific classes of compounds, show no major differences (ranking order) in brain or plasma concentrations between mixture dosing and single compound administration, suggesting that mixture dosing could be applicable to brain penetration studies in the drug discovery phase.
Assuntos
Química Encefálica , Preparações Farmacêuticas/análise , Farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Masculino , Espectrometria de Massas , Ratos , Ratos Sprague-Dawley , Padrões de ReferênciaRESUMO
L-689,502 is a potent inhibitor of HIV-1 protease activity in vitro. Microbial biotransformations of L-689,502 by cultures belonging to the genus Streptomyces sp. were performed. Extracts of culture broths were examined for the production of metabolites of L-689,502 that could inhibit HIV-1 protease activity. One culture, MA 6804 (Streptomyces lavendulae, ATCC 55095), produced L-694,746 that, while being structurally related to L-689,502, is a novel metabolite and a potent inhibitor of HIV-1 protease.
Assuntos
Inibidores da Protease de HIV , HIV-1/enzimologia , Morfolinas/farmacologia , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Sequência de Aminoácidos , Biotransformação , Cromatografia Líquida de Alta Pressão , Cinética , Dados de Sequência Molecular , Estrutura Molecular , Morfolinas/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Pepstatinas/farmacologia , Peptídeos/metabolismo , Streptomyces/metabolismoRESUMO
As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Sulfonamidas/farmacologia , Agonistas Adrenérgicos beta/química , Animais , Cães , Humanos , Indicadores e Reagentes , Cinética , Estrutura Molecular , Oxazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Cães , Relação Dose-Resposta a Droga , Humanos , Infusões Parenterais , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Macaca mulatta , Ligação Proteica , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Taquicardia/induzido quimicamente , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética , BenzenossulfonamidasRESUMO
5-n-Pentyl oxadiazole substituted benzenesulfonamide 8 is a potent and selective beta3 adrenergic receptor agonist (beta3 EC50 = 23 nM, beta1 IC50 = 3000 nM, beta2 IC50 = 3000 nM). The compound has high oral bioavailability in dogs (62%) and rats (36%) and is among the most orally bioavailable beta3 adrenergic receptor agonists reported to date.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/farmacocinética , Oxidiazóis/farmacologia , Oxidiazóis/farmacocinética , Administração Oral , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/química , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Humanos , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/química , Ratos , Relação Estrutura-AtividadeRESUMO
Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacologia , Fármacos Antiobesidade/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/química , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Glicerol/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Macaca mulatta , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Etanolaminas/síntese química , Sulfonamidas/síntese química , Tiazóis/síntese química , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Cricetinae , Humanos , Relação Estrutura-Atividade , BenzenossulfonamidasRESUMO
L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.
Assuntos
Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Tetrazóis/administração & dosagem , Tetrazóis/síntese química , Tetrazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Concentração Inibidora 50 , Cinética , RatosRESUMO
The cyclopentylpropylimidazolidinone L-766,892 is a potent beta3 AR agonist (EC50 5.7 nM, 64% activation) with 420- and 130-fold selectivity over binding to the beta1 and beta2 ARs, respectively. In anesthetized rhesus monkeys, L-766,892 elicited dose-dependent hyperglycerolemia (ED50 0.1 mg/kg) with minimal effects on heart rate.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Ciclopentanos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos beta/metabolismo , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Cricetinae , Ciclopentanos/farmacocinética , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Macaca mulatta , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta 3 , Relação Estrutura-AtividadeRESUMO
The 3-pyridylethanolamine L-757,793 is a potent beta 3 AR agonist (EC50 6.3 nM, 70% activation) with 1,300- and 500-fold selectivity over binding to the beta 1 and beta 2 ARs, respectively. L-757,793 stimulated lipolysis in rhesus monkeys (ED50 0.2 mg/kg) with a maximum response equivalent to that elicited by isoproterenol.