RESUMEN
Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Tiadiazoles/farmacología , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/químicaRESUMEN
Starting from 11ß-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11ß-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Tiadiazoles/síntesis química , Triglicéridos/antagonistas & inhibidores , Células CACO-2 , Ensayos Clínicos como Asunto , Diacilglicerol O-Acetiltransferasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/farmacología , Modelos Moleculares , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/farmacología , Triglicéridos/biosíntesisRESUMEN
A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11ß-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11ß-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Pirazoles/química , Pirrolidinas/química , Urea/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
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
Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.