RESUMEN
Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.
RESUMEN
Prolonged storage of technical abamectin as well as avermectin B1a samples yielded a previously unknown derivative, designated here as compound 1. Detailed NMR analysis and X-ray crystallography allowed us to determine the structure of this compound and revealed the presence of a hydroperoxide group (-OOH) attached stereoselectively with configuration S to the C-8a carbon. This surprising result involves the formation of the peroxide bond in solid crystalline avermectin B1a upon exposure to air with no involvement of light or recognized catalytic factors and is consistent with a topotactic mechanism for the oxidation reaction. Compound 1 is stable in the absence of reducing agents and has potential as a starting point in structural modification of the tetrahydrofuran ring of avermectin B1a. It could also serve as a marker in assessing the quality of stored technical abamectin.
Asunto(s)
Peróxido de Hidrógeno/química , Ivermectina/análogos & derivados , Cristalización , Cristalografía por Rayos X , Ivermectina/química , Ivermectina/farmacología , Espectroscopía de Resonancia Magnética/métodos , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
An atom-environment complexity measure, CA, to assess local changes in complexity during synthetic transformations is described. The complexity measure is based on applying Shannon's equation to the number and diversity of paths up to two bonds in length emanating from an atom node. The method requires no explicit accounting for bond type, stereochemistry, ring membership, symmetry, or molecular size. CA varies with expectation across a number of basic reaction examples and may identify the key disconnections to guide retrosynthesis.
RESUMEN
An atom environment, path based approach to calculating molecular complexity is described. Based on Shannon's equation, the method transforms the number and diversity of paths emanating from an atom to an atom-complexity from which a number of molecular complexity measures are derived. The method is independent of explicitly predefined features such as ring membership, bond types, chirality or symmetry. These path-based measures of complexity can distinguish subtle differences in molecular structure and an application to the visualization of marketed drugs, including a number of biologics, is presented.
Asunto(s)
Preparaciones Farmacéuticas/química , Algoritmos , Entropía , Estructura MolecularRESUMEN
Pharmaceutical companies and other life science R&D organizations routinely work with controlled substances, and must have adequate controls in place to meet the legislative requirements of the countries in which they operate. Controlled substances include a range of narcotics and psychotropic drugs, which are covered by increasingly complex legislation as legislators attempt to keep up with a rapidly changing environment. This legislation must be interpreted and transformed from legal wording into chemical structures to be used effectively. Over the past year a working party of pharmaceutical and technology companies has come together under the umbrella of the Pistoia Alliance to define a Controlled Substance Compliance Service. We describe the benefits of bringing together this group of experts to solve the pre-competitive issue of controlled substance management.
Asunto(s)
Sustancias Controladas , Conducta Cooperativa , Industrias , Legislación de Medicamentos , Narcóticos , Psicotrópicos , InvestigaciónRESUMEN
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Asunto(s)
Descubrimiento de Drogas , Glucocorticoides/síntesis química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis/tratamiento farmacológico , Sitios de Unión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Concentración 50 Inhibidora , Metanol/síntesis química , Metanol/farmacología , Ratones , Modelos Moleculares , Estructura Molecular , Prednisolona/química , Prednisolona/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.
Asunto(s)
Bencimidazoles/química , Fármacos Cardiovasculares/química , Quimasas/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Fármacos Cardiovasculares/síntesis química , Fármacos Cardiovasculares/metabolismo , Dominio Catalítico , Quimasas/química , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/metabolismo , Relación Estructura-ActividadRESUMEN
Representation of synthesis sequences in a network form provides an effective method for the comparison of multiple reaction schemes and an opportunity to emphasize features such as reaction scale that are often relegated to experimental sections. An example of data formatting that allows construction of network maps in Cytoscape is presented, along with maps that illustrate the comparison of multiple reaction sequences, comparison of scaffold changes within sequences, and consolidation to highlight common key intermediates used across sequences. The 17 different synthetic routes reported for strychnine are used as an example basis set. The reaction maps presented required a significant data extraction and curation, and a standardized tabular format for reporting reaction information, if applied in a consistent way, could allow the automated combination of reaction information across different sources.
Asunto(s)
Técnicas de Química Sintética , Modelos Químicos , Estricnina/química , Estricnina/síntesis químicaRESUMEN
Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.
Asunto(s)
Indoles/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Cristalografía por Rayos X , Humanos , Indoles/química , Metaloproteinasa 13 de la Matriz/química , Modelos Moleculares , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Pirazoles/farmacología , Células CACO-2 , Dominio Catalítico , Cristalografía por Rayos X , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos MolecularesRESUMEN
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Quelantes/química , Quelantes/farmacología , Relación Estructura-Actividad , Zinc/químicaRESUMEN
Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
Asunto(s)
Quelantes/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/farmacología , Dominio Catalítico , Quelantes/química , Metaloproteinasa 13 de la Matriz/química , Modelos Moleculares , Inhibidores de Proteasas/química , Unión Proteica , Relación Estructura-ActividadRESUMEN
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Quinolinas/metabolismo , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.
Asunto(s)
Glucocorticoides/agonistas , Ligandos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Glucocorticoides/agonistas , Imitación Molecular , Quinolonas/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Transactivadores/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Aromatasa/metabolismo , Dexametasona/farmacología , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células HeLa , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Quinolonas/síntesis química , Quinolonas/química , Transactivadores/síntesis química , Transactivadores/química , Activación TranscripcionalRESUMEN
A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate.
Asunto(s)
Permeabilidad de la Membrana Celular , Tetrazoles/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Bencimidazoles/química , Bencimidazoles/metabolismo , Células CACO-2 , Línea Celular , Polaridad Celular , Perros , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Losartán/química , Losartán/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Piridinas/química , Piridinas/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Relación Estructura-Actividad , Tetrazoles/química , TransfecciónRESUMEN
We report the discovery of a novel class of glucocorticoid receptor (GR) ligands based on 1,2-dihydroquinoline molecular scaffold. The compounds exhibit good GR binding affinity and selectivity profile against other nuclear hormone receptors.
Asunto(s)
Quinolinas/síntesis química , Quinolinas/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Antiinflamatorios/farmacología , Dexametasona/farmacología , Células HeLa , Humanos , Interleucina-1/farmacología , Interleucina-6/metabolismo , Ligandos , Virus del Tumor Mamario del Ratón/genética , Modelos Moleculares , Estructura Molecular , Regiones Promotoras Genéticas/efectos de los fármacos , Quinolinas/química , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismo , Receptores de Progesterona/efectos de los fármacos , Receptores de Progesterona/metabolismo , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genéticaRESUMEN
An asymmetric route was developed for the synthesis of a class of novel glucocorticoid receptor ligand derivatives 1. The key step of this synthesis involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone precursor. The resulting diastereomers are readily separable and can be converted to the corresponding chiral epoxide and chiral alkyne intermediates (2 and 3). This sequence of reactions is suitable for large-scale preparation of these chiral intermediates and derivatives of 1. The absolute stereochemistry of the biologically active enantiomer of these GR ligands has also been determined.
Asunto(s)
Alcoholes/química , Fluorocarburos/química , Glucocorticoides/síntesis química , Imitación Molecular , Receptores de Glucocorticoides/metabolismo , Alcoholes/farmacología , Alquinos/química , Cristalografía por Rayos X , Fluorocarburos/farmacología , Glucocorticoides/farmacología , Ligandos , Modelos Químicos , EstereoisomerismoRESUMEN
An analysis of the properties of 1791 synthetic, oral drugs approved and/or marketed since 1937 demonstrates that the median molecular weight of oral drugs has increased substantially over the past 60 years. Fewer than 5% of approved/marketed oral drugs have more than 4-H bond donors and just 2% have MW>500 and >3 H-bond donors.