RESUMEN
Evaluation of kinetic parameters of drug-target binding, kon, koff, and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1). The compounds were evaluated in radioligand binding experiments, i.e., displacement, competition association, and washout assays, to evaluate their affinity and binding kinetic parameters. We also linked these pharmacological parameters to the compounds' chemical characteristics, and learned that separate moieties of the molecules governed target affinity and binding kinetics. Among the 29 compounds tested, 28 stood out with high affinity and a long residence time of 87 min. These findings reveal the importance of supplementing affinity data with binding kinetics at transport proteins such as hENT1.
Asunto(s)
Tranportador Equilibrativo 1 de Nucleósido , Tioinosina , Humanos , Transporte Biológico , Tioinosina/metabolismo , Tioinosina/farmacología , Tranportador Equilibrativo 1 de Nucleósido/química , Tranportador Equilibrativo 1 de Nucleósido/metabolismoRESUMEN
Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.
RESUMEN
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Indoles/síntesis química , Diseño de Fármacos , Humanos , Relación Estructura-ActividadRESUMEN
The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles.
RESUMEN
An iron-catalyzed synthesis of sulfur- and sulfone-containing heterocycles is reported. The method is based on the cyclization of readily available substrates and proceeded with high efficiency and diastereoselectivity. A variety of sulfur-containing heterocycles bearing moieties suitable for subsequent functionalization are prepared. Illustrative examples of such postcyclization modifications are also presented.
RESUMEN
An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodynamic equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.
RESUMEN
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Compuestos de Anilina/química , Triazoles/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina/síntesis química , Compuestos de Anilina/metabolismo , Animales , Encéfalo/metabolismo , Diseño de Fármacos , Humanos , Ratones , Ratones Transgénicos , Unión Proteica , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/metabolismoRESUMEN
Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp(3) C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
Asunto(s)
Alcaloides/química , Piperidinas/química , Piridinas/química , Rutenio/química , Catálisis , Hidrogenación , Estructura Molecular , EstereoisomerismoRESUMEN
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Diseño de Fármacos , Piperidinas/farmacología , Triazoles/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Perros , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/química , Piperidinas/metabolismo , Triazoles/química , Triazoles/metabolismoRESUMEN
Transition-metal-catalyzed sp(3) C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru3(CO)12] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru(II)-H species.
Asunto(s)
Aminas/química , Piperidinas/química , Piridinas/química , Rutenio/química , Catálisis , Modelos Moleculares , Estructura MolecularRESUMEN
The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aß42 and Aß40 levels combined with an especially pronounced increase in Aß38 and Aß37 levels while leaving the total levels of amyloid peptides unchanged.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Bencimidazoles/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Imidazoles/síntesis química , Péptidos beta-Amiloides/metabolismo , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Perros , Diseño de Fármacos , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Indazoles/síntesis química , Indazoles/farmacocinética , Indazoles/farmacología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Conformación Molecular , Fragmentos de Péptidos/metabolismo , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.
Asunto(s)
Proteínas del Tejido Nervioso/antagonistas & inhibidores , Pirimidinas/farmacología , Canales Catiónicos TRPC/antagonistas & inhibidores , Tionas/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Animales , Canales de Calcio , Humanos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Tionas/síntesis química , Tionas/químicaAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Enfermedad de Alzheimer/enzimología , Amidas/química , Amidas/farmacología , Amidas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Cinamatos/química , Cinamatos/farmacología , Cinamatos/uso terapéutico , Ensayos Clínicos como Asunto , Ginsenósidos/química , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , EstereoisomerismoRESUMEN
The TRPA1 channel can be considered as a key biological sensor to irritant chemicals. In this paper, the discovery of 11H-dibenz[b,e]azepines (morphanthridines) and dibenz[b,f][1,4]oxazepines is described as extremely potent agonists of the TRPA1 receptor. This has led to the discovery that most of the known tear gases are potent TRPA1 activators. The synthesis and biological activity of a number of substituted morphanthridines and dibenz[b,f][1,4]oxazepines have given insight into the SAR around this class of TRPA1 agonists, with EC(50) values ranging from 1 µM to 0.1 nM. Compounds 6 and 32 can be considered as the most potent TRPA1 agonists known to date, with 6 now being used successfully as a screening tool in the discovery of TRPA1 antagonists. The use of ligands such as 6 and 32 as pharmacological tools may contribute to the basic knowledge of the TRPA1 channel and advance the development of TRPA1 antagonists as potential treatment for conditions involving TRPA1 activation, including asthma and pain.
Asunto(s)
Dibenzazepinas/síntesis química , Dibenzoxazepinas/síntesis química , Proteínas del Tejido Nervioso/agonistas , Oxazepinas/síntesis química , Gases Lacrimógenos/síntesis química , Canales de Potencial de Receptor Transitorio/agonistas , Calcio/metabolismo , Canales de Calcio , Línea Celular , Dibenzazepinas/química , Dibenzazepinas/farmacología , Dibenzoxazepinas/química , Dibenzoxazepinas/farmacología , Fluorometría , Humanos , Espacio Intracelular/metabolismo , Ligandos , Potenciales de la Membrana/efectos de los fármacos , Oxazepinas/química , Oxazepinas/farmacología , Técnicas de Placa-Clamp , Relación Estructura-Actividad , Canal Catiónico TRPA1 , Gases Lacrimógenos/química , Gases Lacrimógenos/farmacologíaRESUMEN
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Modelos Moleculares , Quinazolinas/síntesis química , Secretasas de la Proteína Precursora del Amiloide/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/química , Células CHO , Células CACO-2 , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Conformación Molecular , Mutación , Oligopéptidos/química , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/metabolismo , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
REALISIS is a software system for reagent selection, library design, and profiling, developed to fit the workflow of bench chemists and medicinal chemists. Designed to be portable, the software offers a comprehensive graphical user interface and rapid, integrated functionalities required for reagent retrieval and filtering, product enumeration, and library profiling. REALISIS is component-based, consisting of four main modules: reagent searching; reagent filtering; library enumeration; and library profiling. Each module allows the chemist to access specific functionalities and diverse filtering and profiling mechanisms. By implementing the entire process of reagent selection, library design, and profiling and by integrating all the necessary functionalities for this process, REALISIS cuts the time required to design combinatorial and noncombinatorial libraries from several days to a few hours.