RESUMEN
Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
Asunto(s)
Alanina/análogos & derivados , Amidas/síntesis química , Diabetes Mellitus Experimental/tratamiento farmacológico , Fructosa-Bifosfatasa/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Organofosfonatos/síntesis química , Profármacos/síntesis química , Tiazoles/síntesis química , Administración Oral , Alanina/síntesis química , Alanina/farmacocinética , Alanina/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Organofosfonatos/farmacocinética , Organofosfonatos/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycemia in animal models of type 2 diabetes.
Asunto(s)
Adenosina Monofosfato/química , Bencimidazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Fructosa-Bifosfatasa/antagonistas & inhibidores , Organofosfonatos/química , Adenosina Monofosfato/metabolismo , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hígado/enzimología , Estructura Molecular , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Like most phosphonic acids, the recently discovered potent and selective thiazole phosphonic acid inhibitors of fructose 1,6-bisphosphatase (FBPase) exhibited low oral bioavailability (OBAV) and therefore required a prodrug to achieve oral efficacy. Syntheses of known phosphonate prodrugs did not afford the desired OBAV; hence, a new class of prodrugs was sought. Phosphonic diamides derived from amino acid esters were discovered as viable prodrugs, which met our preset goals: excellent aqueous stability over a wide pH range, benign byproducts (amino acids and low molecular weight alcohols), and most importantly good OBAV leading to robust oral glucose lowering effects. These desirable properties of phosphonic diamides represent significant improvements over existing prodrug classes. Optimization of the diamide prodrugs of phosphonic acid 2a (MB05032) led to the identification of diamide 8 (MB06322), the first reported orally efficacious FBPase inhibitor.