RESUMEN
This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (39). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.
Asunto(s)
Canales Catiónicos TRPM , Canales de Potencial de Receptor Transitorio , Animales , Ratones , Humanos , Canales Catiónicos TRPVRESUMEN
Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression of the thyroid hormone axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-sensitizing activity of RXR agonists but produce substantially reduced side effects. These molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR modulators, we have designed a concise and systematic structure-activity relationship around the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma glucose in the db/db mouse model.
Asunto(s)
Caprilatos/síntesis química , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/síntesis química , Receptores de Ácido Retinoico/efectos de los fármacos , Factores de Transcripción/efectos de los fármacos , Animales , Glucemia/análisis , Caprilatos/química , Caprilatos/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Propionatos/síntesis química , Propionatos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Ratones , Ratones Endogámicos , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Triglicéridos/sangreRESUMEN
Fluorinated trienoic acid analogues of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the position of fluorination, and improvement in pharmacological profile was demonstrated in some cases.