RESUMO
Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Proteínas de Membrana/antagonistas & inibidores , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Asma/tratamento farmacológico , Asma/fisiopatologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/fisiopatologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ensaios Clínicos Controlados como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Leucotrienos/biossíntese , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Integrina alfaVbeta3/metabolismo , Macaca mulatta , Masculino , Naftiridinas/metabolismo , Naftiridinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , RatosRESUMO
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Assuntos
Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Osteoporose/tratamento farmacológico , Receptores de Vitronectina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.
Assuntos
Aminoácidos/química , Ésteres/química , Receptores de Vitronectina/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Ácido Aspártico/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Ésteres/síntese química , Ésteres/farmacocinética , Humanos , Concentração Inibidora 50 , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Ligação Proteica , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.