RESUMEN
We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
Asunto(s)
Descubrimiento de Drogas , Guanidinas/farmacología , Insulina/metabolismo , Compuestos Policíclicos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Glucosa/farmacología , Guanidinas/síntesis química , Guanidinas/química , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Estructura Molecular , Fenotipo , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Ratas , Relación Estructura-ActividadRESUMEN
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Quinolonas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Antivirales/síntesis química , Antivirales/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.
RESUMEN
Complementary stereospecific and stereoconvergent reactions for enantioselective synthesis of 1,3-oxazolidines are reported. In the presence of a rhodium catalyst, reaction of enantioenriched butadiene monoxide with aryl imines is stereospecific (99% ee). Alternatively, the reaction of racemic butadiene monoxide, in the presence of a chiral palladium or nickel catalyst, provides an enantioselective synthesis of 1,3-oxazolidines (up to 94% ee). Synthesis of either the cis- or trans-1,3-oxazolidines is also accomplished under catalyst control.
Asunto(s)
Oxazoles/síntesis química , Catálisis , Cinética , Estructura Molecular , EstereoisomerismoRESUMEN
Conjugate allylation reactions of alpha,beta-unsaturated N-acylpyrroles using allylboronic ester are catalyzed by a palladium complex that is ligated by a bidentate N-heterocyclic carbene. A variety of functional groups are tolerated, and substrates functionalized with electron-withdrawing groups react to afford the highest yields of products. Regioselectivity for 1,4-allylation over 1,2-allylation is demonstrated, and mechanistic experiments are consistent with formation of nucleophilic allylpalladium intermediates.