RESUMEN
Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
Asunto(s)
Compuestos Bicíclicos con Puentes/uso terapéutico , Atrofia Geográfica/tratamiento farmacológico , Degeneración Macular/congénito , Pirroles/uso terapéutico , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Animales , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Perros , Humanos , Degeneración Macular/tratamiento farmacológico , Células de Riñón Canino Madin Darby , Pirroles/química , Pirroles/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Enfermedad de Stargardt , Relación Estructura-ActividadRESUMEN
Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.
Asunto(s)
Diseño de Fármacos , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/patología , Piperidinas/síntesis química , Piperidinas/farmacología , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Animales , Atrofia , Técnicas de Química Sintética , Ligandos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Piperidinas/química , Piperidinas/metabolismo , Prealbúmina/antagonistas & inhibidores , Conformación Proteica , Ratas , Proteínas Plasmáticas de Unión al Retinol/química , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Enfermedad de Stargardt , Relación Estructura-ActividadRESUMEN
Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.
Asunto(s)
Simulación por Computador , Descubrimiento de Drogas , Inhibidores Enzimáticos , Oligopéptidos/química , Tiofenos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Cristalografía por Rayos X , Dexametasona/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Triazinas/síntesis química , Triazinas/farmacología , Animales , Modelos Moleculares , Ratas , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-ActividadRESUMEN
Solid phase, solution, and hybrid approaches to the synthesis of small focused libraries of alpha,alpha-disubstituted-alpha-acylaminoketones have been explored. Solution and hybrid approaches that used support-bound reagents and scavenger resins were the most productive.
RESUMEN
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Éteres/química , Éteres/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/clasificación , Relación Estructura-ActividadRESUMEN
Heterocyclic demonstration libraries for agrochemical screening were prepared from the common intermediates 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (1), using standard solution-phase techniques. A total of 18 screening libraries were prepared in good to excellent yields. Several members of these libraries were active in the first level of agrochemical screening, especially in the fungicide screen.
Asunto(s)
Química Farmacéutica , Técnicas Químicas Combinatorias , Compuestos Heterocíclicos/síntesis química , Nitrilos/química , Piridonas/química , Ciclización , Evaluación Preclínica de Medicamentos , Fungicidas Industriales/análisis , Fungicidas Industriales/farmacología , Peso Molecular , EstereoisomerismoRESUMEN
Two new solid-phase syntheses of substituted pyrazoles are described. The first includes supporting an o-hydroxyacetophenone on Merrifield resin, Vilsmeier-Haack formylation on the methyl group and cyclization with a substituted hydrazine to afford a pyrazole ring with two diversity centers. The second starts from o-hydroxyacetophenone supported on Wang resin, which undergoes a Claisen condensation with a carboxylic acid ester to yield a 1,3-dicarbonyl compound that cyclizes to a pyrazole using a hydrazine. Both methods have been used to synthesize two small pyrazole libraries.
Asunto(s)
Acetofenonas/química , Técnicas Químicas Combinatorias , Pirazoles/síntesis química , Animales , Bioquímica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Fungicidas Industriales/química , Fungicidas Industriales/farmacología , Herbicidas/química , Herbicidas/farmacología , Insecticidas/química , Insecticidas/farmacología , Relación Estructura-ActividadRESUMEN
A library of 35 cis-1-benzoyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolines was prepared. The compounds bore various substitutuents on the benzoyl ring, at the 4-position of the phenylamino ring and at the 6-position of the tetrahydroquinoline ring. The compounds were assayed for their ability to cause expression of a reporter gene downstream of an ecdysone response element in a mammalian cell line engineered to express the ecdysone receptor from Aedes aegypti. In general, compounds with small lipophilic substituents at the meta and para-positions of the benzoyl ring and hydrogen or fluorine at the 4-position of the phenylamino ring and the 6-position of the tetrahydroquinoline ring were the most potent.
Asunto(s)
Ecdisona/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/farmacología , Aedes/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ecdisona/genética , Isomerismo , Ligandos , Quinolinas/química , Receptores de Esteroides/efectos de los fármacos , Receptores de Esteroides/metabolismo , Relación Estructura-Actividad , Activación Transcripcional/efectos de los fármacosRESUMEN
A lead discovery library and a follow-up focused library of alpha-acylaminoketones were designed based on known dibenzoylhydrazine ecdysone agonists, including GS(TM)-E. The compounds were assayed in mammalian cells expressing the ecdysone receptor from Bombyx mori for their ability to cause expression of a reporter gene downstream of an ecdysone response element. The most potent alpha-acylaminoketones were comparable to GS(TM)-E in this assay.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Expresión Génica/efectos de los fármacos , Cetonas/síntesis química , Cetonas/farmacología , Animales , Bombyx/metabolismo , Células Cultivadas , Ecdisona/farmacología , Indicadores y Reactivos , Dosificación Letal Mediana , Ratones , Conformación Molecular , Receptores de Esteroides/antagonistas & inhibidores , Relación Estructura-Actividad , beta-Galactosidasa/biosíntesis , beta-Galactosidasa/genéticaRESUMEN
A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.
Asunto(s)
Amidas/síntesis química , Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Hidrocarburos Fluorados/química , Pirazoles/síntesis química , Tiazoles/síntesis química , Amidas/farmacología , Animales , Antinematodos/síntesis química , Antinematodos/farmacología , Caenorhabditis elegans/efectos de los fármacos , Carbamatos/química , Carbamatos/farmacología , Evaluación Preclínica de Medicamentos , Nematodos/efectos de los fármacos , Pirazoles/farmacología , Tiazoles/farmacologíaRESUMEN
The preparation in multigram scale of two metabolites 3-(3,5-dichloro-4-methyl-benzoylamino)-2-hydroxy-3-methyl-pentanoic acid and 3-(3,5-dichloro-benzoylamino)-3-methyl-2-oxo-butyric acid isolated from soil treated with either Zoxium fungicide or Kerb herbicide was efficiently accomplished using a common 5-step synthetic process starting from easily available raw materials.