RESUMEN
A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Animales , Benzopiranos/farmacología , Carragenina/farmacología , Química Farmacéutica/métodos , Dolor Crónico/tratamiento farmacológico , Diseño de Fármacos , Humanos , Hiperalgesia/tratamiento farmacológico , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Conejos , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Asunto(s)
Acetamidas/uso terapéutico , Antagonistas del Receptor de Bradiquinina B1 , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piperazinas/uso terapéutico , Acetamidas/síntesis química , Acetamidas/química , Animales , Perros , Concentración 50 Inhibidora , Ratones , Modelos Animales , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Conejos , Ratas , Receptor de Bradiquinina B1/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Dolor/tratamiento farmacológico , Sulfonas/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Enfermedad Crónica , Humanos , Conejos , Ratas , Ratas Sprague-Dawley , Sulfonas/administración & dosificaciónRESUMEN
Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/síntesis química , Tiazoles/química , Química Farmacéutica/métodos , Diabetes Mellitus/tratamiento farmacológico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Eritrocitos/enzimología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Infarto del Miocardio/tratamiento farmacológico , Enfermedades Vasculares Periféricas/terapia , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.