RESUMEN
A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
Asunto(s)
Benzamidas/farmacología , Descubrimiento de Drogas , Piperazinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Benzamidas/síntesis química , Benzamidas/química , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Peso Molecular , Piperazinas/síntesis química , Piperazinas/química , Receptores de Neuropéptido Y/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
Asunto(s)
Bencilaminas/química , Bencilaminas/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Sueño/efectos de los fármacos , Animales , Bencilaminas/administración & dosificación , Línea Celular , Diaminas/administración & dosificación , Diaminas/química , Diaminas/farmacología , Antagonistas de los Receptores Histamínicos H3/administración & dosificación , Humanos , Masculino , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Vigilia/efectos de los fármacosRESUMEN
A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Química Farmacéutica/métodos , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Imidazoles/química , Animales , Encéfalo/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cobayas , Antagonistas de los Receptores Histamínicos H3/metabolismo , Humanos , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
Asunto(s)
Receptores Histamínicos H3/química , Receptores Histamínicos H3/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , 5-Hidroxitriptófano/farmacología , Animales , Conducta Animal/efectos de los fármacos , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Ligandos , Ratones , Piperazinas/síntesis química , Piperazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacología , Animales , Cristalografía por Rayos X , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Semivida , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Norepinefrina/metabolismo , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Relación Estructura-Actividad , Tetrahidroisoquinolinas/farmacocinéticaRESUMEN
The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [(11)C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [(11)C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.
Asunto(s)
Radioisótopos de Carbono , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacocinética , Morfolinas/síntesis química , Morfolinas/farmacocinética , Piperidinas/síntesis química , Piperidinas/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Receptores Histamínicos H3/metabolismo , Animales , Autorradiografía , Encéfalo/metabolismo , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Radiofármacos/farmacocinética , Ratas , Distribución TisularRESUMEN
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Unión Competitiva , Línea Celular Tumoral , Quimiotaxis de Leucocito/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Mastocitos/efectos de los fármacos , Ratones , Piperazinas/farmacocinética , Ratas , Receptores Histamínicos , Receptores Histamínicos H4RESUMEN
Starting from 1-methylimidazole, a concise, scalable, three-step synthesis of the title compound is described. The required 2-chloroimidazole was prepared in very good yield by halogen-metal exchange between the 2-lithio derivative and hexachloroethane.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/síntesis química , Imidazoles/química , Imidazoles/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Técnicas Químicas Combinatorias , Estructura MolecularRESUMEN
Histamine is a biogenic amine that plays a host of physiological roles and the three major functions for histamine have been largely defined by the activity of three receptors. The inflammatory wheal and flare response is driven by the H1 receptor [1]. The H2 receptor controls gastric acid secretion in the gut [2]. The H3 receptor is involved in neurotransmitter release in the central nervous system [3]. The recent discovery of the histamine H4 receptor by several groups has lead to the re-evaluation of the physiological role for histamine.
Asunto(s)
Antagonistas de los Receptores Histamínicos/uso terapéutico , Receptores Histamínicos/metabolismo , Animales , Humanos , Ligandos , Piperazina , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologíaRESUMEN
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed.
Asunto(s)
Piperidinas/química , Receptores de Neuropéptido Y/antagonistas & inhibidores , Humanos , Piperidinas/metabolismo , Piperidinas/farmacología , Unión Proteica , Receptores de Neuropéptido Y/metabolismoRESUMEN
The in vitro pharmacological properties of N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide (JNJ-5207787), a novel neuropeptide Y Y(2) receptor (Y(2)) antagonist, were evaluated. JNJ-5207787 inhibited the binding of peptide YY (PYY) to human Y(2) receptor in KAN-Ts cells (pIC(50) = 7.00 +/- 0.10) and to rat Y(2) receptors in rat hippocampus (pIC(50) = 7.10 +/- 0.20). The compound was >100-fold selective versus human Y(1),Y(4), and Y(5) receptors as evaluated by radioligand binding. In vitro receptor autoradiography data in rat brain tissue sections confirmed the selectivity of JNJ-5207787. [(125)I]PYY binding sites sensitive to JNJ-5207787 were found in rat brain regions known to express Y(2) receptor (septum, hypothalamus, hippocampus, substantia nigra, and cerebellum), whereas insensitive binding sites were observed in regions known to express Y(1) receptor (cortex and thalamus). JNJ-5207787 was demonstrated to be an antagonist via inhibition of PYY-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding ([(35)S]GTPgammaS) in KAN-Ts cells (pIC(50) corrected = 7.20 +/- 0.12). This was confirmed auto-radiographically in rat brain sections where PYY-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding was inhibited by JNJ-5207787 (10 microM) in hypothalamus, hippocampus, and substantia nigra. After intraperitoneal administration in rats (30 mg/kg), JNJ-5207787 penetrated into the brain (C(max) = 1351 +/- 153 ng/ml at 30 min) and occupied Y(2) receptor binding sites as revealed by ex vivo receptor autoradiography. Hence, JNJ-5207787 is a potent and selective pharmacological tool available to establish the potential role of central and peripheral Y(2) receptors in vivo.
Asunto(s)
Acrilamidas/farmacología , Piperidinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Autorradiografía , Unión Competitiva , Barrera Hematoencefálica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Piperazinas/química , Piperazinas/farmacología , Receptores de Superficie Celular/efectos de los fármacos , Receptores Acoplados a Proteínas G , Receptores Histamínicos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Cinética , Ligandos , Neuronas/citología , Piperazinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Histamínicos H4 , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.