RESUMEN
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , Urea/farmacología , Amidohidrolasas/metabolismo , Animales , Azetidinas/síntesis química , Azetidinas/química , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/químicaRESUMEN
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
Asunto(s)
Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirimidinas/química , Pirroles/química , Agua/química , Administración Oral , Animales , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HCT116 , Proteínas HSP90 de Choque Térmico/metabolismo , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Relación Estructura-ActividadRESUMEN
We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Azetidinas/química , Azetidinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Urea/química , Animales , Azetidinas/farmacología , Catálisis , Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Ratones Noqueados , Modelos Químicos , Piperidinas/farmacología , Ratas , Receptor Cannabinoide CB1/química , EstereoisomerismoRESUMEN
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Química Farmacéutica/métodos , Inhibidores de Cisteína Proteinasa/síntesis química , Nitrilos/síntesis química , Péptidos/química , Pirimidinas/química , Pirimidinas/síntesis química , Animales , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Conformación Molecular , Nitrilos/farmacología , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Catepsina L , Técnicas Químicas Combinatorias , Cisteína Endopeptidasas , Humanos , Masculino , Estructura Molecular , Esclerosis Múltiple/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirimidinas/sangre , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Hiperalgesia/tratamiento farmacológico , Naftalenos/síntesis química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.