RESUMO
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.
RESUMO
Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.
Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Serina/química , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Descoberta de Drogas , Guanidinas/farmacologia , Insulina/metabolismo , Compostos Policíclicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Glucose/farmacologia , Guanidinas/síntese química , Guanidinas/química , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Fenótipo , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxazóis/síntese química , Catálise , Cinética , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Quinolonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
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.
Assuntos
Compostos Alílicos/química , Paládio/química , Pirróis/química , Acilação , Catálise , Estrutura MolecularRESUMO
Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Fator VIIa/antagonistas & inibidores , Trombose/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Ratos , Relação Estrutura-Atividade , Trombina/antagonistas & inibidoresRESUMO
Synthesis and biological data of a novel selective and efficacious factor IXa inhibitor are described along with its crystal structure in factor VIIa.