RESUMEN
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Indazoles/química , Indazoles/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Animales , Encéfalo/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Indazoles/administración & dosificación , Indazoles/farmacocinética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Masculino , Simulación del Acoplamiento Molecular , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/enzimología , Ratas , Ratas WistarRESUMEN
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Receptores de Glucagón/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Glucemia/metabolismo , Ciclohexanonas/química , Ciclohexanonas/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dieta Alta en Grasa , Descubrimiento de Drogas , Glucagón/farmacología , Ratones , Ratones Endogámicos ICR , Obesidad/tratamiento farmacológico , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/metabolismo , Relación Estructura-ActividadRESUMEN
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Asunto(s)
Fármacos Antidiuréticos/química , Antagonistas de los Receptores de Hormonas Antidiuréticas , Quinolinas/química , Sulfonamidas/química , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/farmacología , Humanos , Quinolinas/síntesis química , Quinolinas/farmacología , Ratas , Receptores de Oxitocina/antagonistas & inhibidores , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Piperazinas/síntesis química , Piperazinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Área Bajo la Curva , Fenómenos Químicos , Química Física , Semivida , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Humanos , Inyecciones Intravenosas , Absorción Intestinal , Conformación Molecular , Piperazinas/farmacocinética , Ratas , Receptores Muscarínicos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/metabolismo , Receptores Muscarínicos/metabolismo , Sitios de Unión , Ligandos , Estructura Molecular , Piperazinas/química , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Relación Estructura-ActividadRESUMEN
A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.