RESUMEN
Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programs by more effectively leveraging available data to guide a molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules within the appropriate chemical space. Many algorithms have been proposed for molecular generation; however, a challenge is how to assess the validity of the resulting molecules. Here, we report three Turing-inspired tests designed to evaluate the performance of molecular generators. Profound differences were observed between the performance of molecule generators in these tests, highlighting the importance of selection of the appropriate design algorithms for specific circumstances. One molecule generator, based on match molecular pairs, performed excellently against all tests and thus provides a valuable component for machine-driven medicinal chemistry design workflows.
Asunto(s)
Algoritmos , Aprendizaje Automático , Química Farmacéutica , Diseño de Fármacos , Humanos , Estructura MolecularRESUMEN
4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Cicloheptanos/química , Morfolinas/química , Fosfatidilinositol 3-Quinasas , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/farmacología , Cicloheptanos/farmacología , Descubrimiento de Drogas/métodos , Humanos , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Relación Estructura-Actividad , Administración por Inhalación , Animales , Fosfatidilinositol 3-Quinasa Clase Ia/química , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Enlace de Hidrógeno , Isoquinolinas/química , Células de Riñón Canino Madin Darby , RatasRESUMEN
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Enfermedades Respiratorias/tratamiento farmacológico , Administración por Inhalación , Animales , Disponibilidad Biológica , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Enfermedades Respiratorias/metabolismo , Relación Estructura-ActividadRESUMEN
The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259.
Asunto(s)
Indazoles/metabolismo , Indazoles/farmacología , Receptor PAR-1/antagonistas & inhibidores , Urea/análogos & derivados , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/química , Conformación Molecular , Receptor PAR-1/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/metabolismo , Urea/farmacologíaRESUMEN
Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM.
Asunto(s)
Lactonas/síntesis química , Lactonas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptor PAR-1/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Lactonas/química , Pulmón/citología , Estructura Molecular , Piridinas/química , Receptor PAR-1/metabolismo , Relación Estructura-ActividadRESUMEN
In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.
Asunto(s)
Química Farmacéutica/educación , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Curriculum , Industria Farmacéutica/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Inhibidores de las Quinasa Fosfoinosítidos-3 , SolubilidadRESUMEN
An efficient two-step synthesis of a wide range of 3-methylene-1,2-diazetidines has been developed through application of a Cu(I)-catalyzed 4-exo ring closure. The double bond of this new class of strained heterocycle can be functionalized in a stereocontrolled manner by using palladium-catalyzed Heck reactions. Moreover, chemoselective reduction of 3-alkylidene-1,2-diazetidines gives access to saturated 1,2-diazetidines and vicinal diamines.
Asunto(s)
Azetidinas/síntesis química , Cobre/química , Paladio/química , Alquilación , Azetidinas/química , Catálisis , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Receptores de Glucocorticoides/agonistas , Tetrahidronaftalenos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Línea Celular , Agonismo Parcial de Drogas , Humanos , Virus del Tumor Mamario del Ratón/genética , Modelos Moleculares , Imitación Molecular , FN-kappa B/genética , Receptores de Glucocorticoides/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
Asunto(s)
Glucocorticoides/agonistas , Pirazoles/química , Receptores de Glucocorticoides/agonistas , Amidas/química , Sitios de Unión , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estereoisomerismo , Esteroides/químicaRESUMEN
Reactions and purifications, including carbon-carbon bond forming reactions, can be carried out on a cellulose support on which the substrates are non-covalently absorbed.
Asunto(s)
Carbono/química , Celulosa/química , Cromatografía en Papel/métodos , Absorción , Cinamatos/aislamiento & purificación , Especificidad por SustratoRESUMEN
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Benzoxazinas/síntesis química , Receptores de Glucocorticoides/agonistas , Tetrahidronaftalenos/síntesis química , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Benzoxazinas/química , Benzoxazinas/farmacología , Unión Competitiva , Línea Celular , Dexametasona/farmacología , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Ratones , Modelos Moleculares , Ensayo de Unión Radioligante , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.
Asunto(s)
Antivirales/síntesis química , Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Infecciones por Orthomyxoviridae/prevención & control , Ácidos Siálicos/química , Ácidos Siálicos/síntesis química , Animales , Antivirales/química , Antivirales/farmacocinética , Antivirales/farmacología , Línea Celular , Cristalización , Dimerización , Guanidinas , Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/virología , Masculino , Membranas Artificiales , Ratones , Modelos Moleculares , Peso Molecular , Infecciones por Orthomyxoviridae/virología , Piranos , Ratas , Ratas Sprague-Dawley , Ácidos Siálicos/farmacocinética , Ácidos Siálicos/farmacología , Estereoisomerismo , Ensayo de Placa Viral , ZanamivirRESUMEN
Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
Asunto(s)
Antivirales/administración & dosificación , Antivirales/farmacología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Neuraminidasa/antagonistas & inhibidores , Orthomyxoviridae/enzimología , Animales , Antivirales/uso terapéutico , Línea Celular , Cromatografía en Gel , Efecto Citopatogénico Viral/efectos de los fármacos , Perros , Inhibidores Enzimáticos/uso terapéutico , Guanidinas , Indicadores y Reactivos , Cinética , Pulmón/metabolismo , Masculino , Ratones , Microscopía Electrónica , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/crecimiento & desarrollo , Infecciones por Orthomyxoviridae/prevención & control , Piranos , Ratas , Ratas Sprague-Dawley , Ácidos Siálicos/química , Ácidos Siálicos/farmacología , Relación Estructura-Actividad , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacos , ZanamivirRESUMEN
Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Lactamas/síntesis química , Elastasa de Leucocito/antagonistas & inhibidores , Pirroles/síntesis química , Pirrolidinas/síntesis química , Sulfonamidas/síntesis química , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Lactamas/farmacocinética , Lactamas/farmacología , Elastasa de Leucocito/sangre , Elastasa de Leucocito/química , Masculino , Modelos Moleculares , Estructura Molecular , Pirroles/farmacocinética , Pirroles/farmacología , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , PorcinosRESUMEN
A flexible, practical, and stereoselective synthesis of enantiomerically pure trans-5-oxohexahydropyrrolo[3,2-b]pyrroles (pyrrolidine-trans-lactams) is described. The key reaction involves addition of Z-ketene acetal 24 to the acyliminium ion derived from 48. This reaction is mediated by BF3·OEt2 and introduces the 6S and 6aS stereocenters stereoselectively. The acyliminium precursor was prepared in four different ways: from racemic 2,4-diaminobutyric acid 8, from (R)-asparagine, from (R)-methionine, and via a crystallization-induced dynamic resolution of a salt of the racemic amine 56. (R)-Methionine is the preferred starting material for the preparation of enantiomerically pure material. The best conditions for addition of the ketene acetal to the acyliminium ion derived from 48 were determined by systematically screening a range of ketene acetals and Lewis acids. The best ketene acetal was Z-(1-ethoxy-3-methylbut-1-enyloxyl)triisopropylsilane 24. In this series, the bulk of the silyl group of the Z-ketene acetal can be correlated with increased 6S isopropyl product. Use of the E-ketene acetal does not lead to a significant change in stereoselectivity for the 6R isopropyl product. In contrast, variation of the Lewis acid has a considerable effect on the product stereochemistry. While BF3·OEt2 gives predominantly 6S,6aS product, AlCl3 and TiCl4 give predominantly mixtures of the 6R,6aS and 6S,6aS products and TMSOTf gives 6aR material with predominantly one unknown isopropyl isomer (trans-lactam numberings used). The synthesis can conveniently be carried out on a large scale to produce multigram quantities of the trans-lactam 28, which is a key precursor of pharmacologically active molecules such as 1, a selective and orally active human neutrophil elastase inhibitor. The overall chemical yield of 1 is 1.3%, corresponding to an average of >70% yield for each of the 14 steps, and the synthesis contains only one chromatographic purification.