RESUMEN
Acromegaly and gigantism are disorders caused by hypersecretion of growth hormone (GH), usually from pituitary adenomas. Although somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists are important therapeutic agents, all of these have issues with their effectiveness, safety, and/or convenience of use. To overcome these, we developed a GH-specific potent neutralizing a mouse monoclonal antibody (mAb) named 13H02. 13H02 selectively bound both to human and monkey GH with high affinity, and strongly inhibited the biological activity of GH in the Nb2 rat lymphoma cell proliferation assay. In hypophysectomized/GH-supplemented rats, a single subcutaneous administration of 13H02 significantly and dose-dependently lowered the serum insulin-like growth factor-1 levels. To pursue the therapeutic potential of this antibody for acromegaly and gigantism, we humanized 13H02 to reduce its immunogenicity and applied a single amino acid mutation in the Fc region to extend its serum half-life. The resulting antibody, Hu-13H02m, also showed GH-specific neutralizing activity, similar to the parental 13H02, and showed improved binding affinity to human FcRn.
Asunto(s)
Acromegalia , Gigantismo , Hormona de Crecimiento Humana , Ratones , Humanos , Femenino , Animales , Ratas , Hormona de Crecimiento Humana/farmacología , Hormona de Crecimiento Humana/metabolismo , Acromegalia/tratamiento farmacológico , Gigantismo/complicaciones , Gigantismo/tratamiento farmacológico , Péptidos Similares a la Insulina , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Flúor/química , Ésteres del Ácido Fórmico/química , Piperazinas/síntesis química , Piperidinas/síntesis química , Acetil-CoA Carboxilasa/clasificación , Administración Oral , Animales , Estructura Molecular , Piperazina , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the structure-based design and synthesis of a novel series of disubstituted (4-piperidinyl)-piperazine derivatives as ACC inhibitors. Our structure-based approach led to the discovery of the indole derivatives 13i and 13j, which exhibited potent in vitro ACC inhibitory activity.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/síntesis química , Piperidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the synthesis and structure-activity relationships of a series of disubstituted (4-piperidinyl)-piperazine derivatives as a new platform for ACC1/2 non-selective inhibitors.