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
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/química , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Oxadiazoles/química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/metabolismo , Proteínas Activadoras de la 5-Lipooxigenasa/química , Animales , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Microsomas Hepáticos/metabolismo , Oxadiazoles/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1-oxobutane-2-sulfonamido) was discovered to be a 690nM antagonist of human CCR10 Ca2+ flux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1-oxobutane-2-sulfonamido (eut-22) that is 300 fold more potent a CCR10 antagonist than 1 and eliminates potential toxicity, mutagenicity, and drug-drug-interaction liabilities often associated with nitroaryls and anilines. eut-22 is highly selective over other GPCR's, including a number of other chemokine receptors. Finally, eut-22 is efficacious in the murine DNFB model of contact hypersensitivity. The efficacy of this compound provides further evidence for the role of CCR10 in dermatological inflammatory conditions.
Asunto(s)
Amidas/farmacología , Dermatitis por Contacto/tratamiento farmacológico , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Receptores CCR10/antagonistas & inhibidores , Amidas/química , Amidas/uso terapéutico , Animales , Ácidos Carboxílicos/química , Línea Celular , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
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
Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Cinética , Espectroscopía de Resonancia Magnética , Modelos Moleculares , ARN Helicasas/antagonistas & inhibidores , Serina Endopeptidasas , Relación Estructura-Actividad , Resonancia por Plasmón de SuperficieRESUMEN
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
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
The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.
Asunto(s)
Carbolinas/química , Carbolinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.