RESUMO
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Proteínas Ativadoras de 5-Lipoxigenase/química , Alcanos/síntese química , Antialérgicos/síntese química , Derivados de Benzeno/síntese química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Alcanos/farmacocinética , Alcanos/farmacologia , Animais , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/farmacologia , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The integrin VLA-4 is implicated in several inflammatory disease states. In search of non-peptidic antagonists of VLA-4, rotational constraints were imposed on the amide bond of prototypical N-sulfonylated dipeptide VLA-4 antagonists. By judicious structural modification of the side chains, trisubstituted imidazoles with moderate binding potencies were obtained, for example, 19, VLA-4 IC(50)=237 nM.
Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Integrina alfa4beta1/antagonistas & inibidores , Estrutura Molecular , Receptores de Antígeno muito Tardio/química , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To determine whether warfarin use, assessed at a single point in time, is associated with bone mineral density (BMD), rates of bone loss, and fracture risk in older men. DESIGN: Secondary analysis of data from a prospective cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Five thousand five hundred thirty-three community-dwelling, ambulatory men aged 65 and older with baseline warfarin use data. MEASUREMENTS: Warfarin use was assessed as current use of warfarin at baseline using an electronic medication coding dictionary. BMD was measured at the hip and spine at baseline, and hip BMD was repeated at a follow-up visit 3.4 years later. Self-reported nonspine fractures were centrally adjudicated. RESULTS: At baseline, the average age of the participants was 73.6 +/- 5.9, and 321 (5.8%) were taking warfarin. Warfarin users had similar baseline BMD as nonusers (n=5,212) at the hip and spine (total hip 0.966 +/- 0.008 vs 0.959 +/- 0.002 g/cm(2), P=.37; total spine 1.079 +/- 0.010 vs 1.074 +/- 0.003 g/cm(2), P=.64). Of subjects with BMD at both visits, warfarin users (n=150) also had similar annualized bone loss at the total hip as nonusers (n=2,683) (-0.509 +/- 0.082 vs -0.421 +/- 0.019%/year, P=.29). During a mean follow-up of 5.1 years, the risk of nonspine fracture was similar in warfarin users and nonusers (adjusted hazard ratio=1.06, 95% confidence interval=0.68-1.65). CONCLUSION: In this cohort of elderly men, current warfarin use was not associated with lower BMD, accelerated bone loss, or higher nonspine fracture risk.
Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Densidade Óssea/efeitos dos fármacos , Fraturas Ósseas/induzido quimicamente , Osteoporose/induzido quimicamente , Varfarina/efeitos adversos , Varfarina/farmacologia , Absorciometria de Fóton , Idoso , Anticoagulantes/uso terapêutico , Seguimentos , Avaliação Geriátrica/métodos , Nível de Saúde , Humanos , Masculino , Estudos Multicêntricos como Assunto , Fatores de Risco , Varfarina/provisão & distribuiçãoRESUMO
VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic beta-amino acids (beta-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (phi) between the amino and the carboxyl termini of the beta-aa. Compound 5 m where the beta-aa is embedded in a bicycle possesses the most preferred phi (120 degrees). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig alpha4beta1 IC50 = 54 nM, rat po F = 49%).
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Integrina alfa4beta1/antagonistas & inibidores , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/farmacocinética , Meia-Vida , Humanos , Indicadores e Reagentes , Integrinas/metabolismo , Células Jurkat , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.
Assuntos
Moduladores de Receptores de Canabinoides/síntese química , Receptor CB1 de Canabinoide/efeitos dos fármacos , Sulfonamidas/síntese química , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Química Encefálica , Moduladores de Receptores de Canabinoides/farmacologia , Humanos , Hipotermia/tratamento farmacológico , Concentração Inibidora 50 , Farmacocinética , Ratos , Receptor CB1 de Canabinoide/agonistas , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Administração Oral , Animais , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , Humanos , Concentração Inibidora 50 , Ligantes , Peso Molecular , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfonamidas/sangue , Sulfonamidas/química , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The alpha(4)beta(1) and alpha(4)beta(7) integrins are implicated in several inflammatory disease states. Systematic SAR studies of an alpha(4)beta(1)-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new alpha(4)beta(7) binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in alpha(4)beta(7) binding affinity while maintaining subnanomolar alpha(4)beta(1) activity, for example 2l, VCAM-Ig alpha(4)beta(1) IC(50)=0.13 nM, VCAM-Ig alpha(4)beta(7) IC(50)=1.92 nM.
Assuntos
Carbamatos/farmacologia , Integrinas/antagonistas & inibidores , Receptores de Retorno de Linfócitos/antagonistas & inibidores , Carbamatos/química , Carbamatos/farmacocinética , Humanos , Integrina alfa4beta1 , Células Jurkat , Relação Estrutura-AtividadeRESUMO
Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , Meia-Vida , Concentração Inibidora 50 , Macaca mulatta , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Integrins alpha9beta1 and alpha4beta1 form a distinct structural class, but while alpha4beta1 has been subjected to extensive study, alpha9beta1 remains poorly characterized. We have used the small molecule N-(benzenesulfonyl)-(L)-prolyl-(L)-O-(1-pyrrolidinylcarbonyl)tyrosine (3) to investigate the biochemical properties of alpha9beta1 and directly compare these properties with those of alpha4beta1. Compound 3 has a high affinity for both integrins with K(D) values of < or =3 and 180 pM for alpha9beta1 in 1 mM Mn2+ (activating) and 1 mM Ca2+ and 1 mM Mg2+ (nonactivating) conditions and < or =5 and 730 pM for alpha4beta1 under the corresponding conditions. Ca2+ treatment promoted the binding of 3 to both integrins (EC50 = 30 microM Ca2+ in both cases). Compound 3 binding to both integrins was also stimulated by the addition of the activating monoclonal antibody TS2/16. These findings indicate that the mechanisms by which metal ions and TS2/16 regulate ligand binding to alpha9beta1 and alpha4beta1 are similar. The binding of 3 to both integrins induced the mAb 9EG7 LIBS epitope, a property consistent with occupancy of the receptor's ligand binding site by 3. But whereas EGTA treatment inhibited the binding of 9EG7 to alpha4beta1, it stimulated the binding of 9EG7 to alpha9beta1. The 9EG7 and TS2/16 effects point to contributions of the beta1-chains on binding. Cross-linking data revealed that the integrin alpha-chains are also involved in binding the small molecule, as stable linkages were observed on both the alpha9 chain of alpha9beta1 and the alpha4 chain of alpha4beta1. Extensive structure-activity analyses with natural and synthetic ligands indicate distinct features of the ligand binding pockets. Most notable was the estimated >1000-fold difference in the affinity of the integrins for VCAM-1, which binds alpha4beta1with an apparent K(D) of 10 nM and alpha9beta1 with an apparent K(D) of >10 microM. Differences were also seen in the binding of alpha9beta1 and alpha4beta1 to osteopontin. Compound 3 competed effectively for the binding of VCAM-1 and osteopontin to both integrins. While these studies show many similarities in the biochemical properties of alpha9beta1 and alpha4beta1, they identify important differences in their structure and function that can be exploited in the design of selective alpha9beta1 and alpha4beta1 inhibitors.