RESUMEN
5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC50 hWBfree of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B4 (LTB4) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB4 levels in humans. Compound 4i is progressed to preclinical in vivo safety studies.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Ciclohexanos/farmacología , Pirazoles/farmacología , Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/toxicidad , Animales , Células CACO-2 , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Ciclohexanos/síntesis química , Ciclohexanos/toxicidad , Perros , Femenino , Humanos , Leucotrieno B4/antagonistas & inhibidores , Masculino , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/toxicidad , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Asunto(s)
Isoindoles/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoindoles/síntesis química , Isoindoles/química , Ratones , Modelos Animales , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110ß isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Plaquetas/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Descubrimiento de Drogas , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacología , Morfolinas/síntesis química , Morfolinas/farmacología , Isoformas de Proteínas/antagonistas & inhibidores , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Animales , Tiempo de Sangría , Perros , Fibrinolíticos/química , Concentración 50 Inhibidora , Resistencia a la Insulina , Estructura Molecular , Morfolinas/química , Pirimidinonas/química , RatasRESUMEN
The discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing inhibitors of Phosphoinositide 3-kinases (PI3K) p110ß isoform is reported. Structure-based optimisation of the original fragment hit resulted in lead compounds with improvements in ligand efficiency, lipophilicity efficiency, p110ß potency and selectivity over p110α.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Unión Proteica/efectos de los fármacos , Isoformas de Proteínas/antagonistas & inhibidores , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología , SolubilidadRESUMEN
Two libraries of alpha-substituted alkynes has been prepared on solid phase using a sequential Sonogashira/Nicholas reaction approach. The scope of nucleophiles in the Nicholas reaction on solid phase has been investigated, including carbon, oxygen, nitrogen, sulfur, fluoride, and hydride nucleophiles. The conditions for the reaction sequence have been optimized in terms of Lewis acid, catalyst for the Sonogashira step, temperature, reaction time, and decomplexation method, enabling the five-step sequence to be performed in 1 day.
Asunto(s)
Alquinos/síntesis química , Química Farmacéutica , Técnicas Químicas Combinatorias , Carbono/química , Catálisis , Fluoruros/química , Hidrocarburos Halogenados/química , Modelos Químicos , Nitrógeno/química , Oxígeno/química , Paladio/química , Tiempo de Reacción , Resinas Sintéticas/química , Azufre/química , TemperaturaRESUMEN
The first example of a Nicholas reaction on solid phase is reported, involving the reaction of cobalt complexes of polymer-bound alkynols with different nucleophiles in the presence of a Lewis acid, to form carbon-oxygen or carbon-carbon bonds.