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1.
J Org Chem ; 89(15): 10912-10918, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39031089

RESUMEN

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.

2.
Eur J Med Chem ; 198: 112373, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32422549

RESUMEN

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.


Asunto(s)
Antineoplásicos/síntesis química , Neoplasias/tratamiento farmacológico , Profármacos/síntesis química , Triptófano/análogos & derivados , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Absorción Intestinal/fisiología , Ratones , Conformación Molecular , Profármacos/administración & dosificación , Profármacos/farmacocinética , Ratas , Triptófano/administración & dosificación , Triptófano/síntesis química , Triptófano/farmacocinética
3.
ACS Med Chem Lett ; 11(4): 541-549, 2020 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-32292562

RESUMEN

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.

4.
J Med Chem ; 62(14): 6705-6733, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31264862

RESUMEN

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.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indoles/farmacología , Animales , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indoles/química , Indoles/farmacocinética , Ratones , Simulación del Acoplamiento Molecular , Ratas , Relación Estructura-Actividad
5.
ACS Comb Sci ; 15(5): 247-54, 2013 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-23514214

RESUMEN

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.


Asunto(s)
Imidoésteres/síntesis química , Ciclización
6.
J Org Chem ; 77(6): 2743-55, 2012 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-22356459

RESUMEN

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.


Asunto(s)
Aminas/síntesis química , Indoles/síntesis química , Malonatos/síntesis química , Aminas/química , Indoles/química , Malonatos/química , Estructura Molecular
7.
J Org Chem ; 74(3): 1141-7, 2009 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-19105638

RESUMEN

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.


Asunto(s)
Alquinos/química , Derivados del Benceno/química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Alquinos/síntesis química , Ciclización , Compuestos Heterocíclicos con 2 Anillos/química , Iminas/síntesis química , Iminas/química
8.
J Org Chem ; 73(17): 6679-85, 2008 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-18683978

RESUMEN

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.


Asunto(s)
Aldehídos/química , Alquinos/química , Fluorenos/síntesis química , Hidrocarburos Halogenados/química , Paladio/química , Catálisis , Modelos Químicos , Estereoisomerismo
9.
J Comb Chem ; 10(5): 658-63, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18671435

RESUMEN

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.


Asunto(s)
Técnicas Químicas Combinatorias/métodos , Isoxazoles/síntesis química , Paladio/química , Acetileno/química , Aminas/química , Ácidos Borónicos/química , Catálisis , Modelos Químicos , Soluciones/química , Estereoisomerismo , Estireno/química
10.
J Org Chem ; 73(17): 6666-70, 2008 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-18665643

RESUMEN

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.


Asunto(s)
Pirazoles/síntesis química , Acilación , Catálisis , Cobre/química , Halogenación , Hidroxilación , Carbonato de Litio/química , Modelos Químicos , Paladio/química , Temperatura , Agua/química
11.
Org Lett ; 10(12): 2409-12, 2008 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-18476707

RESUMEN

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.


Asunto(s)
Azidas/química , Derivados del Benceno/química , Triazoles/síntesis química , Técnicas Químicas Combinatorias , Ciclización , Estructura Molecular
12.
J Org Chem ; 72(25): 9643-7, 2007 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-17979295

RESUMEN

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.


Asunto(s)
Isoxazoles/síntesis química , Sulfonamidas/síntesis química , Catálisis , Ciclización , Isoxazoles/química , Estructura Molecular , Paladio/química , Estereoisomerismo , Sulfonamidas/química
13.
Org Lett ; 7(23): 5203-5, 2005 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-16268538

RESUMEN

[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.


Asunto(s)
Alquinos/química , Hidrocarburos Halogenados/síntesis química , Isoxazoles/síntesis química , Catálisis , Ciclización , Estructura Molecular
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