RESUMEN
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Asunto(s)
Antiinflamatorios/química , Isoindoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Células Sanguíneas/citología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapéutico , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoindoles/farmacocinética , Isoindoles/uso terapéutico , Lipopolisacáridos/farmacología , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Reported herein is the use of catalytic [{Ir(cod)Cl}2 ] to facilitate hydrogen-borrowing reactions of ketone enolates with methanol at 65 °C. An oxygen atmosphere accelerates the process, and when combined with the use of a bulky monodentate phosphine ligand, interrupts the catalytic cycle by preventing enone reduction. Subsequent addition of pro-nucleophiles to the reaction mixture allowed a one-pot methylenation/conjugate addition protocol to be developed, which greatly expands the range of products that can be made by this methodology.
Asunto(s)
Hidrógeno/química , Iridio/química , Cetonas/química , Metanol/química , Catálisis , Metilación , Oxidación-Reducción , TemperaturaRESUMEN
The rhodium-catalyzed methylation of ketones has been accomplished using methanol as the methylating agent and the hydrogen-borrowing method. The sequence is notable for the relatively low temperatures that are required and for the ability of the reaction system to form α-branched products with ease. Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one-pot iridium- and rhodium-catalyzed process.
Asunto(s)
Cetonas/química , Metanol/química , Rodio/química , Catálisis , Iridio/química , Metilación , TemperaturaRESUMEN
This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.
Asunto(s)
Infusiones Intravenosas , Humanos , Método Doble Ciego , Área Bajo la Curva , Voluntarios Sanos , Relación Dosis-Respuesta a DrogaRESUMEN
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , PPAR gamma/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , PPAR gamma/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Asunto(s)
Analgésicos/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Piridazinas/química , Piridinas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/metabolismo , Canales de Calcio Tipo L , Ligandos , Pirazoles/síntesis química , Piridazinas/síntesis química , Piridazinas/uso terapéutico , Piridinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
To understand the relationship between structural properties of the ß2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five ß2 agonists with distinct clinical durations and onsets of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes using magic angle spinning NMR to measure these interactions through both 1H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five ß2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for the lipophilic aromatic rings. Our study elucidates at atomic level that the hydrophobicity and substitution geometry of lipophilic groups play important roles in compound-lipid interactions.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/química , Liposomas/química , Fumarato de Formoterol/química , Interacciones Hidrofóbicas e Hidrofílicas , Indanos/química , Ligandos , Espectroscopía de Resonancia Magnética , Fosfatidilcolinas/química , Quinolonas/química , Xinafoato de Salmeterol/químicaRESUMEN
[reaction: see text] Addition of diethyl thiophosphite to terminal alkenes, in the presence of a radical initiator, followed by deprotonation of the phosphonothioate and reaction with a ketone, offers a concise one-pot approach to substituted alkenes. This novel method, which can incorporate alkylation or acylation steps, can be applied to the stereoselective formation of sterically hindered tri- and tetrasubstituted alkenes.
RESUMEN
(I(t)Pe)AuBr(2)(N-imidate) complexes, prepared in high yield by oxidative bromination, are active catalysts for 1,5-enyne cycloisomerization. An efficient tandem nucleophilic substitution-1,5-enyne cycloisomerization is promoted by these novel Au(III) precatalysts. Catalyst efficacy is affected by the imidate ligand and the silver salt used (e.g. Ag[Al(OC(CF(3))(3))(4)]).
Asunto(s)
Oro/química , Aniones , Catálisis , Ciclización , Isomerismo , Ligandos , Modelos MolecularesRESUMEN
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Benzoatos/química , Células CHO , Cricetinae , Cricetulus , Inflamación/inducido químicamente , Inflamación/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Área Bajo la Curva , Encéfalo/metabolismo , Células CHO , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Indicadores y Reactivos , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP1 receptor antagonists led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high binding efficiency indices.
Asunto(s)
Pirroles/química , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Unión Proteica , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
A novel series of oxadiazole EP1 receptor antagonists was identified by replacing the amide of a known glycine sulfonamide derivative with a 1,3,4-oxadiazole. Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50 of 2.5 nM (pIC50 8.6).
Asunto(s)
Oxadiazoles/química , Oxadiazoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Unión Proteica , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
Asunto(s)
Glicinérgicos/síntesis química , Glicinérgicos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Células CHO , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Dinoprostona/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Indicadores y Reactivos , Subtipo EP1 de Receptores de Prostaglandina ERESUMEN
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.