RESUMEN
Accumulation of amyloid ß peptides (Aß) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aß production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aß reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/uso terapéutico , Piridinas/uso terapéutico , Tiazinas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Animales , Perros , Canal de Potasio ERG1/antagonistas & inhibidores , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Masculino , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas Sprague-Dawley , Tiazinas/síntesis química , Tiazinas/farmacocinéticaRESUMEN
Structure-activity relationships and efforts to optimize the pharmacokinetic profile of isosteric analogs of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among those examined, compound 25 showed potent affinity for cannabinoid receptor 1 (CB1) and receptor 2 (CB2). This compound displayed oral bioavailability and analgesic activity.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Tiazinas/síntesis química , Tiazinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Cinética , Ratones , Modelos Químicos , Ratas , Relación Estructura-Actividad , Tiazinas/farmacocinética , Tiourea/químicaRESUMEN
A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).