RESUMEN
A novel series of adenosine A(2A) receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A(2A) binding affinity, A(1) selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A(2A) antagonist leads.
Asunto(s)
Pirimidinas/farmacología , Receptor de Adenosina A2A/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Receptor de Adenosina A2A/químicaRESUMEN
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Purinonas/síntesis química , Animales , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Purinonas/metabolismo , Purinonas/farmacología , Ratas , Receptor de Adenosina A2A/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Éteres/síntesis química , Sulfonamidas/síntesis química , Animales , Línea Celular , Técnicas Químicas Combinatorias , Humanos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC(50) value at 0.3 microM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders.
Asunto(s)
Inhibidores Enzimáticos/análisis , Inhibidores Enzimáticos/farmacología , Receptor TIE-2/antagonistas & inhibidores , Angiopoyetina 1/farmacología , Animales , Células Cultivadas , Coroides/irrigación sanguínea , Coroides/patología , Neovascularización Coroidal/patología , Colágeno/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Combinación de Medicamentos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Endotelio Vascular/patología , Inhibidores Enzimáticos/química , Humanos , Laminina/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Fosforilación/efectos de los fármacos , Proteoglicanos/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Solubilidad/efectos de los fármacosRESUMEN
The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.
Asunto(s)
Acetamidas/síntesis química , Química Farmacéutica/métodos , Péptidos y Proteínas de Señalización Intracelular/química , Neuropéptidos/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Acetamidas/química , Calcio/química , Línea Celular , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Mutación , Receptores de Orexina , Orexinas , TemperaturaRESUMEN
The discovery and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin (IP) receptor antagonists is described. Analogs disclosed showed high affinity for the IP receptor in human platelet membranes with IC50 values of 0.05-0.50 microM, demonstrated functional antagonism by inhibiting cAMP production in HEL cells with IC50 values of 0.016-0.070 microM, and exhibited significant selectivity versus other prostanoid receptors.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Receptores de Prostaglandina/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Oxazoles/síntesis química , Oxazoles/farmacología , Hidrocarburos Policíclicos Aromáticos/síntesis química , Hidrocarburos Policíclicos Aromáticos/farmacología , Receptores de Epoprostenol , Relación Estructura-ActividadRESUMEN
In a high-throughput screen of four million compounds from combinatorial libraries for small-molecule modulators of the chemokine receptor CXCR3, two classes of receptor agonists, based on tetrahydroisoquinoline and piperidinyl diazepanone templates, were identified. Several of these compounds stimulated calcium flux in HEK293 cells expressing the recombinant human CXCR3 receptor with efficacies and kinetics similar to those of native ligand CXCL11/I-TAC and stimulated chemotaxis of activated human T-cells. The agonist small molecules also inhibited binding of another CXCR3 ligand, CXCL10/IP-10, to the receptor. The response to small-molecule agonists was inhibited by a CXCR3-specific small-molecule antagonist previously identified within the same combinatorial compound collection but structurally unrelated to the agonists. Remarkably, while other, non-amino acid substituents were present in the majority of the library compounds screened, the agonists from both classes contained a positively charged amino acid component, with preference for Arg>Lys, as well as a hydrophobic component.
Asunto(s)
Receptores de Quimiocina/agonistas , Bioquímica/métodos , Quimiocina CXCL10 , Quimiocina CXCL11 , Quimiocinas CXC/química , Quimiocinas CXC/metabolismo , Quimiotaxis , Técnicas Químicas Combinatorias , Relación Dosis-Respuesta a Droga , Humanos , Cinética , Ligandos , Modelos Químicos , Unión Proteica , Receptores CXCR3 , Linfocitos T/metabolismo , Tetrahidroisoquinolinas/farmacologíaRESUMEN
The identification and evaluation of aryl-[1,4]diazepane ureas as functional antagonists of the chemokine receptor CXCR3 are described. Specific examples exhibit IC(50) values of approximately 60 nM in a calcium mobilization functional assay, and dose-dependently inhibit CXCR3 functional response to CXCL11 (interferon-inducible T-cell alpha chemoattractant/I-TAC) as measured by T-cell chemotaxis, with a potency of approximately 100 nM.
Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Urea/química , Calcio/metabolismo , Línea Celular , Química Farmacéutica/métodos , Quimiocina CXCL11 , Quimiocinas CXC/química , Quimiotaxis , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Electrones , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Receptores CXCR3 , Receptores de Quimiocina/química , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Estereoisomerismo , Linfocitos T/citologíaRESUMEN
The regioselectivity of Pd-catalyzed malonate additions and arylations to cycloalkenyl esters can be predicted by completing a stereochemical analysis of the Pd-pi-allyl complex. The Pd-catalyzed malonate additions which have the greatest degree of regioselectivity are in which substituents have a steric influence in blocking the incoming nucleophile. Cyclopentenyl substrates displayed lower regioselectivity than the cyclohexyl counterparts presumably due to increased planarity of the system. Arylations using tin and hypervalent silicon reagents were compared.