Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Bioanalysis ; 13(10): 847-860, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33890503

RESUMEN

The foundation of pharmacokinetics and antidrug antibodies assay robustness relies on the use of high-quality reagents. Over the past decade, there has been increasing interest within the pharmaceutical industry, as well as regulators, on defining best practices and scientific approaches for generation, characterization and handling of critical reagents. In this review, we will discuss current knowledge and practices on critical reagent workflows and state-of-the-art approaches for characterization, generation, stability and storage and how each of these steps can impact ligand-binding assay robustness.


Lay abstract A critical part of clinical development for new biologic drugs is the use of tests known as ligand-binding assay. These assays must be able to accurately measure drug levels and to assess if the biologic drug interacts with the immune system in patients. In order to support patient efficacy and safety, scientists must use state-of-the-art approaches to develop and identify specific reagents for each new biologic drug. This review aims to cover all key steps that are needed to support the quality and performance of the unique components of ligand-binding assays from the beginning of assay development and throughout the entire life-cycle of the biologic drug.


Asunto(s)
Bioensayo/métodos , Indicadores y Reactivos/química , Humanos , Ligandos
3.
J Labelled Comp Radiopharm ; 60(9): 420-430, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28494515

RESUMEN

(S)-6-(2-Hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1) and (4aR,9aS)-1-(1H-benzo[d]midazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1-H-indeno[2,1-b]pyridine-6-carbonitrile hydrochloride (2) are potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type-2 diabetes were prepared labeled with carbon-13 and carbon-14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon-13 synthesis, benzoic-13 C6 acid was converted in 7 steps and in 16% overall yield to [13 C6 ]-(1). Aniline-13 C6 was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6-13 C6 -5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [13 C6 ]-(2) in 19% overall yield. The carbon-14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon-14 labeled methyl magnesium iodide and Suzuki-Miyaura cross coupling via in situ boronate formation. As for the synthesis of [14 C]-(2), 1H-benzimidazole-5-carboxylic-14 C acid was first prepared in 4 steps using potassium cyanide-14 C, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Oxazinas/síntesis química , Oxazinas/química , Oxazinas/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Piridonas/síntesis química , Piridonas/química , Piridonas/farmacología , Estereoisomerismo
4.
J Am Chem Soc ; 138(47): 15473-15481, 2016 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-27794616

RESUMEN

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Piperidinas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Catálisis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hidrogenación , Iridio/química , Conformación Molecular , Paladio/química , Piperidinas/química , Estereoisomerismo
5.
Org Lett ; 18(19): 4920-4923, 2016 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-27661252

RESUMEN

An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.

6.
Chem Sci ; 7(8): 5581-5586, 2016 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28111599

RESUMEN

The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.

7.
Org Lett ; 17(22): 5614-7, 2015 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-26558319

RESUMEN

A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to previously unobtainable, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.


Asunto(s)
Compuestos Aza/química , Aziridinas/síntesis química , Aziridinas/química , Catálisis , Ésteres , Estructura Molecular , Estereoisomerismo
8.
Org Lett ; 16(20): 5494-7, 2014 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-25298301

RESUMEN

A new family of P-chiral P,π-hybrid ligands was prepared from the dihydrobenzooxaphosphole core. These new ligands were demonstrated to be both sterically and electronically tunable at the substituents on the phosphorus atom and the π-system of the ligand. Application of these new ligands to the catalytic asymmetric addition of boronic acids to imine electrophiles was shown to proceed with high levels of enantioinduction.

9.
J Org Chem ; 79(3): 993-1000, 2014 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-24410322

RESUMEN

Synthesis of the electron-rich 2-substituted-6-(phenylsulfonyl)pyridines is presented. A series of air-stable, tunable, P-chiral pyridyl-dihydrobenzooxaphosphole ligands were designed and synthesized by a diastereoselective S(N)Ar substitution of the corresponding sulfonyl pyridines. The ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes with good enantioselectivities.


Asunto(s)
Iridio/química , Compuestos de Fósforo/síntesis química , Piridinas/síntesis química , Alquenos , Catálisis , Hidrogenación , Ligandos , Estructura Molecular , Compuestos de Fósforo/química , Piridinas/química , Estereoisomerismo
10.
Org Lett ; 14(9): 2258-61, 2012 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-22497425

RESUMEN

A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π-π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.


Asunto(s)
Benzoxazoles/química , Compuestos Organofosforados/química , Paladio/química , Catálisis , Técnicas Químicas Combinatorias , Ligandos , Estructura Molecular , Compuestos Organofosforados/síntesis química , Estereoisomerismo
11.
Org Lett ; 13(6): 1366-9, 2011 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-21319836

RESUMEN

In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.


Asunto(s)
Compuestos de Boro/química , Compuestos de Boro/síntesis química , Hidrocarburos Bromados/química , Compuestos Organofosforados/química , Paladio/química , Catálisis , Ligandos , Estructura Molecular , Compuestos Organofosforados/síntesis química
13.
Org Lett ; 12(10): 2334-7, 2010 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-20397735

RESUMEN

Thermal or microwave-mediated heating of 2- or 3-haloindoles with azoles (pK(a) < 8) provides a straightforward, metal-free, and environmentally friendly access to novel 2-(azol-1-yl)indoles. Furthermore, previously unknown 2,3-bis(azolyl-1-yl)indoles can be prepared from 2,3-dihaloindoles by sequential reaction with two distinct azoles. This operationally simple acid-catalyzed process delivers novel indole derivatives in fair to excellent yields and expands the chemical diversity of substitutions that can be introduced on this medicinally important scaffold.


Asunto(s)
Azoles/química , Indoles/química , Indoles/síntesis química , Estructura Molecular , Estereoisomerismo
14.
Org Lett ; 12(9): 2032-5, 2010 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-20337494

RESUMEN

Highly reactive chiral Ru-based catalysts possessing C(1)-symmetric N-heterocyclic carbene ligands adorned with one N-alkyl group and one N-aryl group were evaluated in asymmetric desymmetrizations to form cyclic products possessing a tetrasubstituted olefin.


Asunto(s)
Alquenos/química , Catálisis , Ciclización , Estereoisomerismo
15.
Org Lett ; 12(5): 1104-7, 2010 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-20148522

RESUMEN

A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands was developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of alpha-(acylamino)acrylates and beta-(acylamino)acrylates provided excellent enantioselectivities (up to >99% ee) and reactivities (up to 10,000 TON).


Asunto(s)
Fósforo/química , Rodio/química , Catálisis , Hidrogenación , Ligandos , Modelos Moleculares , Conformación Molecular , Compuestos Organometálicos/química , Estereoisomerismo
16.
Chemistry ; 14(28): 8690-5, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18688840

RESUMEN

In asymmetric olefin metathesis reactions, the addition of halide additives is often required to augment enantioselectivities, despite the fact that the additives result in catalysts with diminished reactivities. The preparation of new chiral Ru-based catalysts was accomplished by exploiting previously reported mechanistic studies. The catalysts possess a high level of reactivity and successfully induce high levels of asymmetry in desymmetrization reactions without the use of halide additives.


Asunto(s)
Alquenos/química , Catálisis , Estereoisomerismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...