RESUMO
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor.
Assuntos
Aminopiridinas/química , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-ret/metabolismo , Aminopiridinas/síntese química , Aminopiridinas/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Mutação , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/toxicidade , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologiaRESUMO
Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [11C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([11C]A1070722) with high affinity to GSK-3 (Ki = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [11C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [11C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Tomografia por Emissão de Pósitrons , Quinolinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Ureia/análogos & derivados , Animais , Mapeamento Encefálico , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Imageamento por Ressonância Magnética , Masculino , Quinolinas/sangue , Compostos Radiofarmacêuticos/sangue , Ureia/sangue , Ureia/síntese químicaRESUMO
Amorphous nanoparticles are able to enhance the kinetic solubility and concomitant dissolution rates of BCS class II and BCS class II/IV molecules due to their characteristic increased supersaturation levels, smaller particle size and greater surface area. A DoE approach was applied to investigate formulation and spray drying process parameters for the preparation of spray dried amorphous ABT-102 nanoparticles. Stability studies were performed on the optimized formulations to monitor physical and chemical changes under different temperature and humidity conditions. SLS/soluplus and SLS/PVP K25 were the best stabilizer combinations. Trehalose was used to prevent nanoparticle aggregation during spray drying. Particle size distribution, moisture content, PXRD, PLM, FTIR and in vitro dissolution were utilized to characterize the spray dried nanoparticle formulations. The formulations prepared using soluplus showed enhanced dissolution rate compared to those prepared using PVP K25. Following three months storage, it was observed that the formulations stored at 4°C were stable in terms of particle size distribution, moisture content, and crystallinity, whereas those stored at 25°C/60%RH and 40°C/75%RH were unstable. A predictive model to prepare stable solid spray dried amorphous ABT-102 nanoparticles, incorporating both formulation and process parameters, was successfully developed using multiple linear regression analysis.
Assuntos
Química Farmacêutica/métodos , Indazóis/síntese química , Nanopartículas/química , Tamanho da Partícula , Ureia/análogos & derivados , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Ureia/síntese química , Difração de Raios XRESUMO
A facile, efficient and environmentally-friendly protocol has been developed for the green synthesis of CuO nanoparticles (NPs) by aqueous extract of Gundelia tournefortii as a mild, renewable and non-toxic reducing agent. CuO NPs were characterized by SEM, TEM, XRD, EDS, FT-IR and UV-vis spectroscopy. More importantly, the green synthesized CuO NPs presented excellent catalytic activity for reduction of 4-nitrophenol and synthesis of N-monosubstituted ureas via hydration of cyanamides with the aid of acetaldoxime as an effective water surrogate in ethanol as a green solvent. The catalyst was easily separated and the recovered catalyst was reused many times without any significant loss of the catalytic activity.
Assuntos
Asteraceae/química , Cobre/química , Química Verde , Nanopartículas/química , Nitrofenóis/química , Ureia/síntese química , Catálise , Cianamida/química , Reutilização de Equipamento , Nanopartículas/ultraestrutura , Oxirredução , Oximas/química , Extratos Vegetais/química , Ureia/análogos & derivadosRESUMO
We report the green synthesis of silver nanoparticles by using Euphorbia condylocarpa M. bieb root extract for the synthesis of N-monosubstituted ureas in water. UV-visible studies show the absorption band at 420 nm due to surface plasmon resonance (SPR) of the silver nanoparticles. This reveals the reduction of silver ions (Ag+) to silver (Ago) which indicates the formation of silver nanoparticles (Ag NPs). This method has the advantages of high yields, simple methodology and easy work up.
Assuntos
Química Verde/métodos , Nanopartículas Metálicas/química , Fenômenos Ópticos , Prata/química , Ureia/síntese química , Água/química , Catálise , Euphorbia/química , Nanopartículas Metálicas/ultraestrutura , Extratos Vegetais/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified.
Assuntos
Amidas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Amidas/síntese química , Amidas/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos/metabolismo , Ligação Proteica , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/metabolismo , Ureia/síntese química , Ureia/química , Ureia/metabolismoRESUMO
The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.
Assuntos
Desenho de Fármacos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Ureia/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Naftalenos/química , Naftalenos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Pirazóis/química , Pirazóis/metabolismo , Piridinas/química , Piridinas/metabolismo , Fator de Necrose Tumoral alfa/sangue , Ureia/síntese química , Ureia/toxicidadeRESUMO
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.
Assuntos
Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Humanos , Naftalenos/síntese química , Naftalenos/química , Naftalenos/metabolismo , Prolina/química , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/metabolismo , Receptores CCR3/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/metabolismoRESUMO
Induction of HSPs is a natural response of stressed cells that protects against many insults including acute ischemia. TRC051384, a novel compound belonging to substituted 2-propen-1-one class is a potent inducer of heat shock protein 70 (HSP70). The aim of this study was to investigate the ability of TRC051384 in reducing neuronal injury and disability upon delayed treatments (4 and 8 hours post ischemia onset) in a rat model of transient cerebral ischemia. Focal cerebral ischemia was produced in rats by occluding the MCA using the intra luminal suture technique. Rats subjected to 2 hours focal cerebral ischemia were administered by intra-peritoneal route, TRC051384 or vehicle every 2 hours for 48 hours, from 4th hour or 8th hour after onset of ischemia. Progression of infarct and edema was assessed up to 48 hours post ischemic insult using magnetic resonance imaging and the neurological disability and survival studied till 7 days. Here we show for the first time that treatment with TRC051384 significantly reduces stroke associated neuronal injury (87% reduction in area of penumbra recruited to infarct, and 25% reduction in brain edema) and disability in a rat model of transient ischemic stroke even when administered 8 hours post onset of ischemia. Significant improvement in survival (50% by day 2 and 67.3% by day 7) was observed with TRC051384 treatment initiated at 4 hours after ischemia onset. Induction of HSP70 by TRC051384 involves HSF1 activation and results in elevated chaperone and anti-inflammatory activity. These results show that TRC051384 has the potential to be developed as a novel pharmacological agent for the treatment of ischemic stroke.
Assuntos
Proteínas de Choque Térmico HSP70/biossíntese , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Morfolinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Piridinas/uso terapêutico , Ureia/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP72/metabolismo , Células HeLa , Fatores de Transcrição de Choque Térmico , Humanos , Infarto da Artéria Cerebral Média/mortalidade , Infarto da Artéria Cerebral Média/patologia , Inflamação/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Morfolinas/síntese química , Morfolinas/farmacologia , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Fatores de Transcrição/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Ureia/síntese química , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Ureia/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Piridinas/química , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
Assuntos
Aminas/química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Compostos de Fenilureia/química , Sulfonamidas/química , Ureia/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Ureia/síntese química , Ureia/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
In this study, difatty acyl urea has been successfully synthesized from corn oil using sodium ethoxide as a catalyst. Ethyl fatty ester and glycerol were produced as by-products. In this reaction, corn oil was refluxed with urea in ethanol. The highest conversion percentage (78%) was obtained when the process was carried out for 8 hours using urea to corn oil ratio of 5.6: 1.0 at 78 degrees C. Both difatty acyl urea and ethyl fatty ester have been characterized using elemental analysis, Fourier transform infrared (FTIR) spectroscopy and (1)H nuclear magnetic resonance (NMR) technique.
Assuntos
Óleo de Milho/química , Ureia/química , Ureia/síntese química , Catálise , Ésteres/química , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
Assuntos
Amidas/química , Antivirais/química , Inibidores de Serina Proteinase/química , Sulfonamidas/química , Ureia/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Simulação por Computador , Cães , Avaliação Pré-Clínica de Medicamentos , Proteínas de Escherichia coli , Haplorrinos , Humanos , Proteínas de Membrana , Modelos Moleculares , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Ureia/síntese química , Ureia/química , Ureia/farmacocinética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
In the course of our studies on the isolation of bioactive compounds from the roots of Moringa oleifera, a traditional herb in southeast Asia, rare aurantiamide acetate 4 and 1,3-dibenzyl urea 5 have been isolated and characterized. And also, this is the first report of isolation from this genus. Isolated compound inhibited the production of TNF-alpha and IL-2; further compound 5 showed significant analgesic activities in a dose dependant manner. These findings may help in understanding the mechanism of action of this traditional plant leading to control of activated mast cells on inflammatory conditions like arthritis, for which the crude extract has been used.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Dipeptídeos/síntese química , Moringa oleifera/química , Ureia/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Dipeptídeos/farmacologia , Interleucina-2/antagonistas & inibidores , Mastócitos/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Ratos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ureia/farmacologiaRESUMO
3-Haloacylamino benzoylureas (3-HBUs) consist of a new family of tubulin ligands that kill cancer cells through mitotic arrest. In exploring the structure-activity relationship (SAR), 17 analogues defined through variations of formylurea at the 1-position of the aromatic ring were synthesized. SAR analysis revealed that (i) the p-pi conjugation between the aromatic ring and formylurea was essential; (ii) suitable aryl substitutions at the N'-end increased anticancer activity with a mechanism different from that of parent compounds; and (iii) introduction of pyridyl at the N'-end provided an opportunity of making soluble salts to improve bioavailability. Among the analogues, 16c bearing 3,4,5-trimethoxyphenyl and 16g bearing 2-pyridyl at the N'-end showed an enhanced activity and were active in hepatoma cells that were resistant to tubulin ligands including the parent compounds. Furthermore, 16c and 16g killed cancer cells with a mechanism independent of mitotic arrest, indicating a change of action mode.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Ureia/análogos & derivados , Ureia/química , Ureia/síntese química , Antineoplásicos/farmacologia , Ácidos Carboxílicos/química , Proliferação de Células , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Mitose , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The synthesis of nine new mono- and bis-O-phenylisouronium compounds (2, 6b-10b and 12b-14b) and their Boc-protected isourea precursors (2a, 6a-10a and 12a-14a) is described. The carbodiimide 4, which was formed, had been suggested as the reactive intermediate species and driving force of the reaction. All final substrates were tested as potential alpha(2)-ARs ligands in human brain tissue by means of radioligand binding experiments and were compared to the potential antidepressant 1, as well as other related guanidine containing derivatives.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Antidepressivos/síntese química , Encéfalo/metabolismo , Sulfetos/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Sais/síntese química , Sais/química , Sais/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Ureia/químicaRESUMO
A facile, one-pot synthesis of thio and selenourea derivatives from amines using tetrathiomolybdate 1 and tetraselenotungstate 2 as sulfur and selenium transfer reagents, respectively, is reported. The compounds were tested for their activity as urease inhibitors and some of the compounds showed potent activity in the nanomolar range towards jack bean urease.
Assuntos
Molibdênio/química , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/farmacologia , Tioureia/síntese química , Tioureia/farmacologia , Ureia/análogos & derivados , Urease/antagonistas & inibidores , Canavalia/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos Organosselênicos/química , Tioureia/química , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.
Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor TIE-2/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Área Sob a Curva , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HT29 , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Modelos Moleculares , Transplante de Neoplasias , RNA/biossíntese , RNA/genéticaRESUMO
A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Cicloexanos/química , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Ureia/síntese química , Ureia/farmacologia , Amidas/química , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/químicaRESUMO
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.