RESUMO
We report the discovery of a convenient and efficient method for the synthesis of highly substituted 1,6-naphthyridines. A tandem nitrile hydration/cyclization procedure was developed to access 1,6-naphthyridine-5,7-diones under mild conditions. Subsequently, we have found that ditriflation of these intermediates provides 1,6-naphthyridine-5,7-ditriflates which are bench-stable but highly reactive intermediates that can be engaged in one-pot difunctionalization reactions leading to diverse drug-like products in rapid fashion.
RESUMO
A series of different prodrugs of indoximod, including estesrs and peptide amides were synthesized with the aim of improving its oral bioavailability in humans. The pharmacokinetics of prodrugs that were stable in buffers, plasma and simulated gastric and intestinal fluids was first assessed in rats after oral dosing in solution or in capsule formulation. Two prodrugs that produced the highest exposure to indoximod in rats were further tested in Cynomolgus monkeys, a species in which indoximod has oral bioavailability of 6-10% and an equivalent dose-dependent exposure profile as humans. NLG802 was selected as the clinical development candidate after increasing oral bioavailability (>5-fold), Cmax (6.1-3.6 fold) and AUC (2.9-5.2 fold) in monkeys, compared to equivalent molar oral doses of indoximod. NLG802 is extensively absorbed and rapidly metabolized to indoximod in all species tested and shows a safe toxicological profile at the anticipated therapeutic doses. NLG802 markedly enhanced the anti-tumor responses of tumor-specific pmel-1 T cells in a melanoma tumor model. In conclusion, NLG802 is a prodrug of indoximod expected to increase clinical drug exposure to indoximod above the current achievable levels, thus increasing the possibility of therapeutic effects in a larger fraction of the target patient population.
Assuntos
Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Pró-Fármacos/síntese química , Triptofano/análogos & derivados , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Composição de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Absorção Intestinal/fisiologia , Camundongos , Conformação Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Ratos , Triptofano/administração & dosagem , Triptofano/síntese química , Triptofano/farmacocinéticaRESUMO
A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug-drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme.
RESUMO
A novel class of 5-substituted 5H-imidazo[5,1-a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo[5,1-a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.
Assuntos
Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indóis/farmacologia , Animais , Cães , Desenho de Fármacos , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/química , Indóis/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The solution-phase parallel synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki-Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks.
Assuntos
Imidoésteres/síntese química , CiclizaçãoRESUMO
Pyrido[1,2-a]indoles are known as medicinally and pharmaceutically important compounds, but there is a lack of efficient methods for their synthesis. We report a convenient and efficient route to these privileged structures starting from easily accessible 2-substituted pyridines and aryne precursors. A small library of compounds has been synthesized utilizing the developed method, affording variously substituted pyrido[1,2-a]indoles in moderate to good yields.
Assuntos
Aminas/síntese química , Indóis/síntese química , Malonatos/síntese química , Aminas/química , Indóis/química , Malonatos/química , Estrutura MolecularRESUMO
The relative reactivity of various functional groups toward alkyne electrophilic cyclization reactions has been studied. The required diarylalkynes have been prepared by consecutive Sonogashira reactions of appropriately substituted aryl halides and competitive cyclizations have been performed using I(2), ICl, NBS and PhSeCl as electrophiles. The results indicate that the nucleophilicity of the competing functional groups, polarization of the alkyne triple bond, and the cationic nature of the intermediate are the most important factors in determining the outcome of these reactions.
Assuntos
Alcinos/química , Derivados de Benzeno/química , Compostos Heterocíclicos com 2 Anéis/síntese química , Alcinos/síntese química , Ciclização , Compostos Heterocíclicos com 2 Anéis/química , Iminas/síntese química , Iminas/químicaRESUMO
The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.
Assuntos
Técnicas de Química Combinatória/métodos , Isoxazóis/síntese química , Paládio/química , Acetileno/química , Aminas/química , Ácidos Borônicos/química , Catálise , Modelos Químicos , Soluções/química , Estereoisomerismo , Estireno/químicaRESUMO
Fluoren-9-ones and derivatives are readily prepared in good yields by the annulation of in situ generated arynes by 2-haloarenecarboxaldehydes in the presence of a palladium catalyst.
Assuntos
Aldeídos/química , Alcinos/química , Fluorenos/síntese química , Hidrocarbonetos Halogenados/química , Paládio/química , Catálise , Modelos Químicos , EstereoisomerismoRESUMO
A number of new functionally substituted 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles have been prepared in moderate to excellent yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li2CO3 at room temperature to provide 1-acyl-4-iodo-1H-pyrazoles.
Assuntos
Pirazóis/síntese química , Acilação , Catálise , Cobre/química , Halogenação , Hidroxilação , Carbonato de Lítio/química , Modelos Químicos , Paládio/química , Temperatura , Água/químicaRESUMO
A variety of substituted benzotriazoles have been prepared by the [3 + 2] cycloaddition of azides to benzynes. The reaction scope is quite general, affording a rapid and easy entry to substituted, functionalized benzotriazoles under mild conditions.
Assuntos
Azidas/química , Derivados de Benzeno/química , Triazóis/síntese química , Técnicas de Química Combinatória , Ciclização , Estrutura MolecularRESUMO
A large number of functionally substituted 2-alkyn-1-one O-methyl oximes have been cyclized under mild reaction conditions in the presence of ICl to give the corresponding 4-iodoisoxazoles in moderate to excellent yields. The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles, including valdecoxib.
Assuntos
Isoxazóis/síntese química , Sulfonamidas/síntese química , Catálise , Ciclização , Isoxazóis/química , Estrutura Molecular , Paládio/química , Estereoisomerismo , Sulfonamidas/químicaRESUMO
[reaction: see text] A variety of 3,5-disubstituted 4-halo(seleno)isoxazoles are readily prepared in good to excellent yields under mild reaction conditions by the reaction of 2-alkyn-1-one O-methyl oximes with ICl, I2, Br2, or PhSeBr.