RESUMEN
A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.
Asunto(s)
Hipersensibilidad/tratamiento farmacológico , Indoles/clasificación , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Compuestos de Espiro/clasificación , Compuestos de Espiro/farmacología , Animales , Sitios de Unión , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Diseño de Fármacos , Humanos , Indoles/química , Inflamación/tratamiento farmacológico , Masculino , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The metabolic stability of benzoxazinone derivatives, a potent series of NPY Y5 antagonists, has been investigated. This study resulted in the identification of the structural moieties prone to metabolic transformations and which strongly influenced the in vitro half-life. This provides opportunities to optimize the structure of this new class of NPY Y5 antagonists.
Asunto(s)
Oxazinas/metabolismo , Oxazinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Estructura Molecular , Oxazinas/química , Receptores de Neuropéptido Y/metabolismo , Relación Estructura-ActividadRESUMEN
Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.