RESUMO
Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
Assuntos
Analgésicos/uso terapêutico , Catepsinas/antagonistas & inibidores , Hiperalgesia/tratamento farmacológico , Imunossupressores/uso terapêutico , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Encéfalo/metabolismo , Catepsinas/genética , Catepsinas/metabolismo , Linhagem Celular , Citocinas/imunologia , Temperatura Alta , Humanos , Hiperalgesia/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/imunologia , Traumatismos dos Nervos Periféricos/imunologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Nervo Isquiático/lesões , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Toxoide Tetânico/administração & dosagem , TatoRESUMO
Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED50 values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.
Assuntos
Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Antipruriginosos/farmacologia , Ácidos Araquidônicos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase/farmacologia , Glicerídeos/metabolismo , Humanos , Hidrólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Células PC-3 , Dor/tratamento farmacológico , Dor/metabolismo , Piperidinas/farmacologia , Prostaglandinas/farmacologia , Ratos , Ratos Sprague-Dawley , RoedoresRESUMO
The serine hydrolase monoacylglycerol lipase (MGLL) converts the endogenous cannabinoid receptor agonist 2-arachidonoylglycerol (2-AG) and other monoacylglycerols into fatty acids and glycerol. Genetic or pharmacological inactivation of MGLL leads to elevation in 2-AG in the central nervous system and corresponding reductions in arachidonic acid and eicosanoids, producing antinociceptive, anxiolytic, and antineuroinflammatory effects without inducing the full spectrum of psychoactive effects of direct cannabinoid receptor agonists. Here, we report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, 28 (ABX-1431). Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class. In vivo, 28 inhibits MGLL activity in rodent brain (ED50 = 0.5-1.4 mg/kg), increases brain 2-AG concentrations, and suppresses pain behavior in the rat formalin pain model. ABX-1431 (28) is currently under evaluation in human clinical trials.
Assuntos
Descoberta de Drogas , Monoacilglicerol Lipases/antagonistas & inibidores , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologia , Piperazina/farmacologia , Piperazinas/farmacologia , Pirrolidinas/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Terapia de Alvo Molecular , Dor/tratamento farmacológico , Dor/enzimologia , Piperazina/farmacocinética , Piperazina/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Distribuição TecidualRESUMO
Novel classes of tetrahydropyrido-pyrazole thioether amines and arylalkynes that display potency against human Cathepsin S have been previously reported. Here, key pharmacophoric elements of these two classes are merged, and SAR investigations of the P4 region are described, in conjunction with re-optimization of the P5 and P1/P1'/P3 regions. Identification of meta-substituted arylalkynes with good potency and improved solubility is described.
Assuntos
Alcinos/química , Alcinos/farmacologia , Catepsinas/antagonistas & inibidores , Catepsinas/química , Pirazóis/química , Pirazóis/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
Assuntos
Benzofuranos/química , Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.
Assuntos
Compostos Aza/farmacologia , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Animais , Compostos Aza/síntese química , Compostos Aza/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Epóxido Hidrolases/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Antagonistas dos Receptores Histamínicos/química , Camundongos , Receptores Histamínicos , Receptores Histamínicos H4RESUMO
The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/antagonistas & inibidores , Descoberta de Drogas , Indanos/farmacologia , Animais , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Indanos/síntese química , Indanos/química , Camundongos , Estrutura Molecular , Canais de Potássio/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Indicadores e Reagentes , Indóis/farmacocinética , Isomerismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.
Assuntos
Acetamidas/farmacologia , Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores de Proteases/farmacologia , Pirazóis/farmacologia , Sulfetos/farmacologia , Acetamidas/química , Catepsinas/química , Linhagem Celular , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/químicaRESUMO
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Catepsinas/metabolismo , Linhagem Celular , Humanos , Relação Estrutura-AtividadeRESUMO
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores de Proteases/farmacologia , Pirazóis/farmacologia , Sulfetos/farmacologia , Sítios de Ligação , Catepsinas/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/químicaRESUMO
LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
Assuntos
Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Catálise , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-AtividadeRESUMO
We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.
Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Inibidores da Topoisomerase II , Antibacterianos/síntese química , Antibacterianos/química , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.
Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Pirazóis/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase IIRESUMO
Leukotriene A(4) hydrolase (LTA(4)H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B(4), which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA(4)H (IC(50), approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA(4)H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB(4) production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED(50), 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB(4) production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A(4). The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB(4), LTC(4), and LXA(4) production. Although zileuton inhibited LTB(4) production in the peritonitis model more effectively than the LTA(4)H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton- versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA(4) levels in the presence of the LTA(4)H inhibitor. The selective inhibition of LTB(4) production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA(4), may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB(4)-mediated inflammatory diseases.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzotiazóis/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase , Piperidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Ácido Araquidônico/farmacologia , Líquido Ascítico/efeitos dos fármacos , Líquido Ascítico/metabolismo , Benzotiazóis/metabolismo , Benzotiazóis/uso terapêutico , Cães , Orelha/patologia , Edema/patologia , Edema/prevenção & controle , Eicosanoides/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Feminino , Humanos , Hidroxiureia/metabolismo , Hidroxiureia/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Leucotrieno B4/metabolismo , Leucotrieno C4/metabolismo , Lipoxinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Infiltração de Neutrófilos/efeitos dos fármacos , Peritonite/metabolismo , Peritonite/patologia , Peritonite/prevenção & controle , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMO
A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
Assuntos
Compostos Bicíclicos com Pontes/química , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Piperidinas/química , Animais , Sítios de Ligação , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Camundongos , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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
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
By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benzimidazolinone series of compounds which display single digit nanomolar NK(1)/NK(2) affinity and near micromolar binding for the NK(3) receptor.