RESUMEN
Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.
Asunto(s)
Carbono/química , Técnicas de Química Sintética , Química Farmacéutica/métodos , Éteres/síntesis química , Ácidos Carboxílicos/química , ElectroquímicaRESUMEN
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.
Asunto(s)
Proteínas Tirosina Quinasas/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Agammaglobulinemia Tirosina Quinasa , Animales , Células Cultivadas , Ligandos , Poliubiquitina/metabolismo , Ratas , TermodinámicaRESUMEN
C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.
Asunto(s)
Aminas/síntesis química , Técnicas Electroquímicas , Aminación , Aminas/química , Catálisis , Teoría Funcional de la Densidad , Cinética , Estructura MolecularRESUMEN
A practical electrochemical oxidation of unactivated C-H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively functionalize "deep-seated" methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.
Asunto(s)
Carbono/química , Hidrógeno/química , Técnicas Electroquímicas , Estructura Molecular , Oxidación-ReducciónRESUMEN
Here we describe the development of novel methods for compound evaluation and prioritization based on the structure-activity relationship matrix (SARM) framework. The SARM data structure allows automatic and exhaustive extraction of SAR patterns from data sets and their organization into a chemically intuitive scaffold/functional-group format. While SARMs have been used in the retrospective analysis of SAR discontinuity and identifying underexplored regions of chemistry space, there have been only a few attempts to apply SARMs prospectively in the prioritization of "close-in" analogs. In this work, three new ways of prioritizing virtual compounds based on SARMs are described: (1) matrix pattern-based prioritization, (2) similarity weighted, matrix pattern-based prioritization, and (3) analysis of variance based prioritization (ANV). All of these methods yielded high predictive power for six benchmark data sets (prediction accuracy R2 range from 0.63 to 0.82), yielding confidence in their application to new design ideas. In particular, the ANV method outperformed the previously reported SARM based method for five out of the six data sets tested. The impact of various SARM parameters were investigated and the reasons why SARM-based compound prioritization methods provide higher predictive power are discussed.
Asunto(s)
Descubrimiento de Drogas/métodos , Informática/métodos , Relación Estructura-ActividadRESUMEN
Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides).
Asunto(s)
Aminas/química , Níquel/química , Alcoholes/química , Aminación , Compuestos de Bencilo/química , Catálisis , Técnicas Electroquímicas , ElectrodosRESUMEN
Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.
Asunto(s)
Encéfalo , Diseño de Fármacos , Receptor Muscarínico M4 , Receptor Muscarínico M4/metabolismo , Receptor Muscarínico M4/agonistas , Regulación Alostérica/efectos de los fármacos , Humanos , Animales , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Relación Estructura-Actividad , Ratas , Cricetulus , Células CHO , Agonistas Muscarínicos/farmacología , Agonistas Muscarínicos/síntesis química , Agonistas Muscarínicos/química , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismoRESUMEN
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Asunto(s)
Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Monobactamas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Monobactamas/síntesis química , Monobactamas/química , Ratas , Relación Estructura-ActividadRESUMEN
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
RESUMEN
The polyethylene glycol (PEG) moiety has become increasingly important in medicinal chemistry. Herein, we describe the PEG functionalization of amines via hydrogen borrowing reductive amination. This was accomplished using the [Ru(p-cymene)Cl2]2 catalyst and phosphorus-containing ligand dppf or DPE to yield a variety of PEGylated primary and secondary amine products. Furthermore, we illustrate the utility of this method with the synthesis of quetiapine (Seroquel) in 62% isolated yield.
RESUMEN
An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 µmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability.
Asunto(s)
Loratadina/análogos & derivados , Loratadina/farmacocinética , Relación Estructura-Actividad , Animales , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Dimetilsulfóxido/química , Perros , Descubrimiento de Drogas/métodos , Antagonistas de los Receptores Histamínicos H1 no Sedantes/química , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacología , Humanos , Enlace de Hidrógeno , Inactivación Metabólica , Loratadina/química , Espectroscopía de Resonancia Magnética , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Conejos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Animales , Antibacterianos/química , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Imidazoles/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Piridinas/química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Sepsis/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.
RESUMEN
An unprecedented cheap, mild and easy methodology for an intramolecular Minisci reaction based on a hydrogen atom transfer (HAT) initiated hydrofunctionalization of olefins was developed. The method is suitable for the construction of unusual dihydropyrano-pyridine and 1,2,3,4-tetrahydronaphthiridine structures and, unlike most similar reactions, does not require exclusion of air from the reaction medium.
RESUMEN
Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.
Asunto(s)
Interleucina-17/antagonistas & inhibidores , Interleucina-17/química , Péptidos Cíclicos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Algoritmos , Sitios de Unión , Células Cultivadas , Diseño de Fármacos , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Simulación de Dinámica Molecular , Péptidos Cíclicos/química , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.
Asunto(s)
Hidrolasas/metabolismo , Lisofosfolipasa/antagonistas & inhibidores , Serina/metabolismo , Animales , Cristalización , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacología , Humanos , Lisofosfolipasa/químicaRESUMEN
Reported here are procedures for a one-pot oxidation and rearrangement of propargylamines to synthesize enaminones, with supporting mechanistic studies. Also reported are the extended one-pot syntheses of pyrazoles, including celecoxib and various heterocyclic compounds.
Asunto(s)
Pargilina/análogos & derivados , Propilaminas/química , Pirazoles/síntesis química , Sulfonamidas/síntesis química , Catálisis , Celecoxib , Técnicas Químicas Combinatorias , Estructura Molecular , Oxidación-Reducción , Pargilina/química , Pirazoles/química , Sulfonamidas/químicaRESUMEN
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and ß-lactam core structures. Results from drug sensitivity studies with ß-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Asunto(s)
Bacterias Gramnegativas/metabolismo , Péptidos/metabolismo , Receptores de Superficie Celular/metabolismo , Sideróforos/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Péptidos/efectos de los fármacos , Péptidos Cíclicos , beta-Lactamasas/metabolismoRESUMEN
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry additional risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.
Asunto(s)
Inhibidores Enzimáticos/química , Glutatión/química , Diseño de Fármacos , Glutatión/metabolismo , Humanos , Cinética , Espectrometría de Masas , Resonancia Magnética Nuclear Biomolecular , Preparaciones Farmacéuticas/químicaRESUMEN
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.