RESUMO
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Indazóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Humanos , Indazóis/farmacocinética , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Tetrazóis/síntese química , Tetrazóis/farmacologia , Amidas/química , Amidas/farmacocinética , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.
Assuntos
Aminas/química , Benzofenonas/química , Benzofenonas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzofenonas/síntese química , Linhagem Celular , Cães , Humanos , Estrutura Molecular , Ratos , Receptor B1 da Bradicinina/metabolismo , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Isoxazóis/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Isoxazóis/farmacocinética , Macaca mulatta , Receptor de Pregnano X , Ratos , Ratos Sprague-DawleyRESUMO
A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
Assuntos
Amidas/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Amidas/síntese química , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Cinética , Neuropeptídeos/química , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Prolina/síntese química , RatosRESUMO
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy.
Assuntos
Amidas/química , Antagonistas de Receptor B1 da Bradicinina , Animais , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica/métodos , Cloro/química , Ciclopropanos/química , Desenho de Fármacos , Humanos , Modelos Químicos , Fenol/química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Selective bradykinin (BK) B(1) receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure-activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B(1) receptor antagonists.
Assuntos
Analgésicos/química , Anti-Inflamatórios não Esteroides/química , Antagonistas de Receptor B1 da Bradicinina , Cicloexanos/química , Hidrocarbonetos Fluorados/química , Piridinas/química , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Cicloexanos/síntese química , Cicloexanos/farmacologia , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor B1 da Bradicinina/genética , Relação Estrutura-AtividadeRESUMO
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Assuntos
Acetamidas/síntese química , Amidas/síntese química , Compostos de Aminobifenil/síntese química , Benzoatos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Ciclopropanos/síntese química , Medula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/farmacocinética , Benzoatos/farmacologia , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
We report the critical residues for the interaction of the kinins with human bradykinin receptor 1 (B1) using site-directed mutagenesis in conjunction with molecular modeling of the binding modes of the kinins in the homology model of the B1 receptor. Mutation of Lys118 in transmembrane (TM) helix 3, Ala270 in TM6, and Leu294 in TM7 causes a significant decrease in the affinity for the peptide agonists des-Arg10kallidin (KD) and des-Arg9BK but not the peptide antagonist des-Arg10Leu9KD. In contrast, mutations in TM2, TM3, TM6, and TM7 cause a significant decrease in the affinity for both the peptide agonists and the antagonist. These data indicate that the B1 bradykinin binding pocket for agonists and antagonists is similar, but the manners in which they interact with the receptor do not completely overlap. Therefore, there is a potential to influence the receptor's ligand selectivity.
Assuntos
Cininas/química , Cininas/metabolismo , Modelos Moleculares , Receptor B1 da Bradicinina/química , Receptor B1 da Bradicinina/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Membrana Celular/química , Membrana Celular/metabolismo , Sequência Conservada , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação/genética , Ligação Proteica , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Receptor B1 da Bradicinina/genética , Alinhamento de SequênciaAssuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Benzamidas/química , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sulfonamidas/química , Animais , Antipsicóticos/síntese química , Camundongos , Camundongos Endogâmicos DBA , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of 2,3-diaminopyridine bradykinin B(1) antagonists was modified to mitigate the potential for bioactivation. Removal of the 3-amino group and incorporation of basic 5-piperazinyl carboxamides at the pyridine 5-position provided compounds with high affinity for the human B(1) receptor.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Piperazinas/farmacologia , Humanos , Modelos Moleculares , Piperazinas/químicaRESUMO
Antagonists of the B1 bradykinin receptor (B1R), encoded by the BDKRB1 gene, offer the promise of novel therapeutic agents for inflammatory and neuropathic pain. However, the in vivo characterization of the pharmacodynamics of B1R antagonists is hindered by the low level of B1R expression in healthy tissue and the profound species selectivity exhibited by many compounds for the B1R. To circumvent these issues we generated two genetically engineered rodent models. The first is a transgenic rat over-expressing the human B1R under the control of the neuronal-specific enolase promoter; we previously reported the utility of this model in assessing human B1R receptor occupancy in the central nervous system of the rat. The second model, reported here, utilized gene-targeting by homologous recombination to replace the genomic coding sequence for the endogenous mouse B1R with that of the human B1R. The mRNA expression profile of the humanized Bdkrb1 (hBkdrb1) allele is similar to that of the mouse Bdkrb1 (mBkdrb1) in the wild-type animal. Furthermore, in vitro assays indicate that tissues isolated from the humanized mouse possess pharmacological properties characteristic of the human B1R. Therefore, we have generated a humanized B1R mouse model that is suitable for testing the efficacy of human B1R-selective compounds.
Assuntos
Acetamidas/farmacologia , Receptor B1 da Bradicinina , Sulfonas/farmacologia , Acetamidas/química , Animais , Antagonistas de Receptor B1 da Bradicinina , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Estrutura Molecular , RNA Mensageiro/genética , Receptor B1 da Bradicinina/genética , Receptor B1 da Bradicinina/fisiologia , Sulfonas/química , Transcrição GênicaRESUMO
Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antagonistas de Receptor B1 da Bradicinina , Ciclopropanos/síntese química , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Disponibilidade Biológica , Ciclopropanos/química , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Conformação Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.
Assuntos
Amidas/farmacocinética , Antagonistas de Receptor B1 da Bradicinina , Naftalenos/farmacocinética , Medição da Dor/métodos , Pirrolidinas/farmacocinética , Medula Espinal/efeitos dos fármacos , Amidas/administração & dosagem , Animais , Carragenina/administração & dosagem , Carragenina/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrofisiologia/métodos , Pé , Membro Posterior , Temperatura Alta/efeitos adversos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Hipersensibilidade/etiologia , Hipersensibilidade/fisiopatologia , Injeções Intravenosas , Injeções Espinhais , Masculino , Morfina/farmacologia , Naftalenos/administração & dosagem , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Medula Espinal/fisiologiaRESUMO
SAR study of the biphenyl region of 2,3-diaminopyridine bradykinin B1 antagonists was investigated with non-aromatic carbo- and heterocyclic rings. A piperidine ring was found to be a good replacement for the proximal phenyl ring while replacement of the distal phenyl was optimal with a cyclohexyl group leading to a dramatic improvement in affinity for the B1 receptor.
Assuntos
Aminopiridinas/síntese química , Antagonistas de Receptor B1 da Bradicinina , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Bradicinina/antagonistas & inibidores , Humanos , Farmacocinética , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure-activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described.
Assuntos
Aminopiridinas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Piridinas/síntese química , Aminopiridinas/química , Desenho de Fármacos , Humanos , Cinética , Modelos Moleculares , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
Assuntos
Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores da Bradicinina , Animais , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Humanos , Biologia Molecular , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/agonistas , Receptor B2 da Bradicinina/metabolismo , Receptores da Bradicinina/classificação , Receptores da Bradicinina/genética , Receptores da Bradicinina/fisiologia , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Non-peptide antagonists of the oxytocin receptor (OTR) have been developed to prevent pre-term labour. The benzoxazinone-based antagonists L-371,257 and L-372,662 display pronounced species-dependent pharmacology with respect to selectivity for the OTR over the V(1a) vasopressin receptor. Examination of receptor sequences from different species identified Ala(318) in helix 7 of the human OTR as a candidate discriminator required for high affinity binding. The mutant receptor [A318G]OTR was engineered and characterised using ligands representing many different chemical classes. Of all the ligands investigated, only the benzoxazinone-based antagonists had decreased affinity for [A318G]OTR. Molecular modelling revealed that Ala(318) provides a direct hydrophobic contact with a methoxy group of L-371,257 and L-372,662.
Assuntos
Oxazinas/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/química , Alanina/genética , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzoxazinas , Ligação Competitiva , Glicina/genética , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Oxazinas/química , Piperidinas/química , Mutação Puntual/genética , Piridinas/química , Receptores de Ocitocina/genética , Receptores de Vasopressinas/genética , Relação Estrutura-AtividadeRESUMO
We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca2+ assays more than 7-fold with an EC50 value of approximately 27 nM. At 1 microM, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left. At higher concentrations, CDPPB exhibited agonist-like activity on cells expressing mGluR5. No other activity was observed on any other mGluR or cell type at concentrations up to 10 microM. CDPPB had no effect on [3H]quisqualate binding to mGluR5 but did compete for binding of [3H]methoxyPEPy, an analog of the selective mGluR5 negative allosteric modulator MPEP. CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamine-induced deficits in prepulse inhibition in rats, two models sensitive to antipsychotic drug treatment. These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo. These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents.