RESUMEN
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/química , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.
Asunto(s)
Diseño de Fármacos , Receptor Cannabinoide CB2/agonistas , Diseño Asistido por Computadora , Humanos , Ligandos , Microsomas Hepáticos/metabolismo , Unión Proteica , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.
Asunto(s)
Ácidos Pipecólicos/química , Piperidinas/química , Receptor Cannabinoide CB2/agonistas , Tiazinas/química , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Semivida , Humanos , Ligandos , Masculino , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ácidos Pipecólicos/farmacocinética , Ácidos Pipecólicos/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Unión Proteica , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-Actividad , Tiazinas/farmacocinética , Tiazinas/uso terapéuticoRESUMEN
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
Asunto(s)
Isoxazoles/química , Prolina/química , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptor Cannabinoide CB2/agonistas , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Semivida , Humanos , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Ligandos , Masculino , Microsomas Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapéutico , Unión Proteica , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacocinética , Ácido Pirrolidona Carboxílico/uso terapéutico , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
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
A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.
Asunto(s)
Azepinas/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Azepinas/química , Microsomas Hepáticos/metabolismo , Ratas , Ratas WistarRESUMEN
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacología , Indoles/química , Indoles/farmacología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animales , Células HeLa , Humanos , Ratones , 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
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
Asunto(s)
Acetamidas/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Descubrimiento de Drogas , Inhibidores de la Lipooxigenasa/farmacología , Oxadiazoles/farmacología , Acetamidas/síntesis química , Acetamidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Modelos Moleculares , Conformación Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
Asunto(s)
Catepsinas/síntesis química , Dipéptidos/síntesis química , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Linfocitos B/efectos de los fármacos , Unión Competitiva , Catepsinas/química , Catepsinas/farmacología , Línea Celular , Cristalografía por Rayos X , Dipéptidos/química , Dipéptidos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.
Asunto(s)
Huesos/efectos de los fármacos , Receptores de Glucocorticoides/agonistas , Animales , Línea Celular Tumoral , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Relación Estructura-ActividadRESUMEN
A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.
RESUMEN
Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Receptores de Glucocorticoides/agonistas , Esteroides/química , Tejido Adiposo/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Aromatasa/biosíntesis , Aromatasa/genética , Inhibidores de la Aromatasa/farmacología , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Células Cultivadas , Inducción Enzimática , Femenino , Humanos , Enlace de Hidrógeno , Insulina/sangre , Interleucina-1/farmacología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Interleucina-6/genética , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/efectos adversos , Piridinas/farmacología , Pirroles/efectos adversos , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
Alpha-methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog synthesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these compounds will be discussed.
Asunto(s)
Receptores de Glucocorticoides/efectos de los fármacos , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Triptaminas/síntesis química , Triptaminas/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Progesterona/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Química Farmacéutica/métodos , Nitrilos/química , Dominio Catalítico , Dipéptidos/química , Diseño de Fármacos , Humanos , Modelos Químicos , Conformación Molecular , Nitrilos/clasificación , Péptidos/química , Piperidinas/química , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
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
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.