RESUMO
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.
Assuntos
Benzamidas/farmacologia , Descoberta de Drogas , Piperazinas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Benzamidas/síntese química , Benzamidas/química , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Peso Molecular , Piperazinas/síntese química , Piperazinas/química , Receptores de Neuropeptídeo Y/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzilaminas/química , Benzilaminas/farmacologia , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Animais , Benzilaminas/administração & dosagem , Linhagem Celular , Diaminas/administração & dosagem , Diaminas/química , Diaminas/farmacologia , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Humanos , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Vigília/efeitos dos fármacosRESUMO
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.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/síntese química , Imidazóis/química , Animais , Encéfalo/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cobaias , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Ligantes , Modelos Químicos , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptores Histamínicos H3/química , Receptores Histamínicos H3/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , 5-Hidroxitriptofano/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Ligantes , Camundongos , Piperazinas/síntese química , Piperazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Cristalografia por Raios X , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Meia-Vida , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Norepinefrina/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacocinéticaRESUMO
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.
Assuntos
Radioisótopos de Carbono , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacocinética , Morfolinas/síntese química , Morfolinas/farmacocinética , Piperidinas/síntese química , Piperidinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Autorradiografia , Encéfalo/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição TecidualRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Indóis/síntese química , Indóis/farmacocinética , Indóis/farmacologia , Mastócitos/efeitos dos fármacos , Camundongos , Piperazinas/farmacocinética , Ratos , Receptores Histamínicos , Receptores Histamínicos H4RESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/síntese química , Imidazóis/química , Imidazóis/síntese química , Receptores Histamínicos H3/efeitos dos fármacos , Técnicas de Química Combinatória , Estrutura MolecularRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/uso terapêutico , Receptores Histamínicos/metabolismo , Animais , Humanos , Ligantes , Piperazina , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologiaRESUMO
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.
Assuntos
Piperidinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Humanos , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Receptores de Neuropeptídeo Y/metabolismoRESUMO
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.
Assuntos
Acrilamidas/farmacologia , Piperidinas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Autorradiografia , Ligação Competitiva , Barreira Hematoencefálica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores Acoplados a Proteínas G , Receptores Histamínicos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Cinética , Ligantes , Neurônios/citologia , Piperazinas/metabolismo , Ensaio Radioligante , Ratos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Histamínicos H4 , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
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.