RESUMEN
Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.
Asunto(s)
Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Humanos , Necrosis , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Relación Estructura-ActividadRESUMEN
Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed 'Markovnikov' additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.
Asunto(s)
Alquenos/química , Fosfatos/química , Ácidos/química , Aminación , Catálisis , Deuterio , Indoles/química , Espectrometría de Masas , Modelos QuímicosRESUMEN
Reactions proceeding through cationic intermediates that lack a Lewis or Brønsted basic site present a challenge for traditional asymmetric catalysis based on chiral metals or organocatalysts. We present an enantioselective ring opening of tetrasubstituted meso-aziridinium ions with alcohol nucleophiles proceeding through a chiral ion pair with a binaphthol-phosphate anion. The reaction is initiated by silver-induced ring closure of beta-chloroamines using the Ag salt of the chiral anion as in situ generated catalyst. Use of insoluble Ag2CO3 as silver source is essential to obtain high enantioselectivity; we believe the chiral phosphate acts as a "chiral anion phase transfer catalyst" to bring silver ion into the organic phase. The chiral anion concept can also be extended to the related asymmetric opening of meso-episulfonium ions generated by protonation of trichloroacetimidates vicinal to sulfides.
Asunto(s)
Aziridinas/química , Compuestos de Sulfonio/química , Aniones/química , Carbonatos/química , Ciclización , Compuestos de Plata/química , EstereoisomerismoRESUMEN
Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells.
Asunto(s)
Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/metabolismo , Transporte de Proteínas/efectos de los fármacos , Proteínas ras/metabolismo , Células Cultivadas , Inhibidores Enzimáticos/química , Modelos Biológicos , Prenilación de Proteína , Transducción de Señal/efectos de los fármacosRESUMEN
Despite the tremendous advances of the past four decades, chemists are far from being able to use chiral catalysts to control the stereoselectivity of any desired reaction. New concepts for the construction and mode of operation of chiral catalysts have the potential to open up previously inaccessible reaction space. The recognition and categorization of distinct approaches seems to play a role in triggering rapid exploration of new territory. This Review both reflects on the origins as well as details a selection of the latest examples of an area that has advanced considerably within the past five years or so: the use of chiral anions in asymmetric catalysis. Defining reactions as involving chiral anions is a difficult task owing to uncertainties over the exact catalytic mechanisms. Nevertheless, we attempt to provide an overview of the breadth of reactions that could reasonably fall under this umbrella.
RESUMEN
The discovery of distinct modes of asymmetric catalysis has the potential to rapidly advance chemists' ability to build enantioenriched molecules. As an example, the use of chiral cation salts as phase-transfer catalysts for anionic reagents has enabled a vast set of enantioselective transformations. Here, we present evidence that a largely overlooked analogous mechanism wherein a chiral anionic catalyst brings a cationic species into solution is itself a powerful method. The concept is applied to the enantioselective fluorocyclization of olefins with a cationic fluorinating agent and a chiral phosphate catalyst. The reactions proceed in high yield and stereoselectivity, especially considering the scarcity of alternative approaches. This technology can in principle be applied to the large portion of reaction space that uses positively charged reagents and reaction intermediates.
RESUMEN
Substitution of the C-11 aniline of mifepristone can provide compounds with altered pharmacokinetic and pharmacodynamic (PK/PD) profiles that may find use for new indications. The development of new steroid intermediates and specialized library synthesis methods were required to enable the efficient preparation of structurally complex C-11 modified mifepristone analogs.
Asunto(s)
Química Farmacéutica/métodos , Mifepristona/análogos & derivados , Mifepristona/síntesis química , Biblioteca de Péptidos , Compuestos de Anilina/química , Antagonistas de Hormonas/síntesis química , Mifepristona/química , Modelos BiológicosRESUMEN
Traditionally, transition metal-catalyzed enantioselective transformations rely on chiral ligands tightly bound to the metal to induce asymmetric product distributions. Here we report high enantioselectivities conferred by a chiral counterion in a metal-catalyzed reaction. Two different transformations catalyzed by cationic gold(I) complexes generated products in 90 to 99% enantiomeric excess with the use of chiral binaphthol-derived phosphate anions. Furthermore, we show that the chiral counterion can be combined additively with chiral ligands to enable an asymmetric transformation that cannot be achieved by either method alone. This concept of relaying chiral information via an ion pair should be applicable to a vast number of metal-mediated processes.
Asunto(s)
Alcadienos/química , Catálisis , Oro/química , Compuestos Orgánicos de Oro/química , Fosfatos/química , Compuestos de Plata/química , Estereoisomerismo , Aminación , Aniones/química , Ciclización , Ligandos , SolventesRESUMEN
Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacocinética , Hígado/metabolismo , Mifepristona/análogos & derivados , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Glucocorticoides/síntesis química , Ratas , Ratas EndogámicasRESUMEN
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.