RESUMEN
A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.
Asunto(s)
Analgésicos/uso terapéutico , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Piridinas/uso terapéutico , Receptores Purinérgicos P2X3/metabolismo , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacocinética , Perros , Diseño de Fármacos , Interacciones Farmacológicas , Glucuronosiltransferasa/antagonistas & inhibidores , Semivida , Hiperbilirrubinemia/prevención & control , Estructura Molecular , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
Asunto(s)
Analgésicos/farmacología , Benzoxazoles/farmacología , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Sulfonamidas/farmacología , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Benzoxazoles/administración & dosificación , Benzoxazoles/química , Disponibilidad Biológica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Formaldehído/administración & dosificación , Humanos , Ratones , Estructura Molecular , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Dolor/inducido químicamente , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.
Asunto(s)
Transportadoras de Casetes de Unión a ATP , Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Proteínas Bacterianas , Lipopolisacáridos , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Animales , Lipopolisacáridos/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Ratones , Humanos , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/metabolismo , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Pruebas de Sensibilidad MicrobianaRESUMEN
The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 µM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.
Asunto(s)
Descubrimiento de Drogas , Fenómenos Electrofisiológicos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Canales Iónicos Sensibles al Ácido , Animales , Estructura Molecular , Fragmentos de Péptidos , Ratas , Bibliotecas de Moléculas Pequeñas , Canales de SodioRESUMEN
[reaction: see text] Additions of chiral allenylzinc and indium reagents to N-Boc alaninal were examined as a possible route to a C20-C26 segment of superstolide A. Allenylzinc reagents, prepared in situ by palladiozincation of (R)- and (S)-5-pivalyloxy-3-butyn-2-ol mesylate, showed excellent reagent control to afford the anti,syn and anti,anti diastereomers as the nearly exclusive adducts.
Asunto(s)
Alanina/análogos & derivados , Macrólidos/síntesis química , Piranos/síntesis química , Tetrahidronaftalenos/síntesis química , Alanina/química , Animales , Catálisis , Ciclización , Indicadores y Reactivos , Macrólidos/química , Estructura Molecular , Poríferos/química , Piranos/química , Estereoisomerismo , Tetrahidronaftalenos/químicaRESUMEN
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.
RESUMEN
Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.