RESUMEN
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-ß peptide (Aß) is critical for Alzheimer's disease (AD) pathogenesis. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aß-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aß reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aß reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neuronas/efectos de los fármacos , Adulto , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/análisis , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Ácido Aspártico Endopeptidasas/análisis , Células Cultivadas , Corteza Cerebral/citología , Cristalografía/métodos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Inhibidores Enzimáticos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Modelos Químicos , Mutación/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Tiazinas/farmacología , Tiazinas/uso terapéutico , Factores de Tiempo , Adulto JovenRESUMEN
Session 1 of the 2010 STP/IFSTP Joint Symposium on Toxicologic Neuropathology, titled "Fundamentals of Neurobiology," was organized to provide a foundation for subsequent sessions by presenting essential elements of neuroanatomy and nervous system function. A brief introduction to the session titled "Introduction to Correlative Neurobiology" was provided by Dr. Greg Hall (Eli Lilly and Company, Indianapolis, IN). Correlative neurobiology refers to considerations of the relationships between the highly organized and compartmentalized structure of nervous tissues and the functioning within this system.