RESUMO
We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure, considerations were made as to how physicochemical properties and safety concerns relate to structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with a pharmacokinetic profile suitable for topical application.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/agonistas , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cães , Relação Dose-Resposta a Droga , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Estrutura Molecular , Ratos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.
Assuntos
Anti-Inflamatórios/química , Receptores de Glucocorticoides/agonistas , Tetra-Hidronaftalenos/química , Amino Álcoois/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Genes Reporter , Meia-Vida , Células HeLa , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ligação Proteica , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Ativação Transcricional/efeitos dos fármacosRESUMO
The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with reduced activity in a transactivation assay, hinting at an improved therapeutic window over corticosteroids.
Assuntos
Anti-Inflamatórios/química , Quinolinas/química , Receptores de Glucocorticoides/agonistas , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/genética , Humanos , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores de Glucocorticoides/metabolismo , Ativação TranscricionalRESUMO
Smoke inhalation injury is often complicated with pneumonia, which frequently leads to subsequent development of sepsis. Excessive NO has been shown to mediate many sepsis-related pathological responses. In the present study, we used our well-established ovine smoke inhalation and pneumonia/sepsis model to examine the hypothesis that neuronal NO synthase (NOS) may be primarily responsible for these pathological alterations. We report the beneficial effects of the specific neuronal NOS (nNOS) inhibitor ZK234238. Adult female sheep were surgically prepared for the study. After 5 to 7 days' recovery, sheep were anesthetized and given double injury: insufflation of 48 breaths of cotton smoke (<40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa (5 x 10(11) colony-forming units) into each sheep's lung via tracheostomy tube. All sheep were mechanically ventilated and fluid resuscitated by lactated Ringer's solution. Sheep were randomly allocated into groups: control (injured not treated, n = 6) and treated (injured, but treated with ZK234238, n = 4). Continuous infusion of ZK234238 (100 microg x kg(-1) x h(-1)) was started 1 h after insult. ZK234238 attenuated the hypotension (at 18 and 24 h) and fall in systemic vascular resistance (at 24 h) seen in control animals. ZK234238 significantly inhibited increased fluid accumulation as well as increased plasma nitrate/nitrite 24 h after injury. Neuronal NOS inhibition significantly reduced lung water content and attenuated inflammatory indices such as lung tissue myeloperoxidase activity, IL-6 mRNA, and reactive nitrogen species. The above results suggest that the nNOS-derived NO may be involved in the pathophysiology of sepsis-related multiorgan dysfunction.
Assuntos
Óxido Nítrico Sintase Tipo I/metabolismo , Sepse/enzimologia , Animais , Modelos Animais de Doenças , Feminino , Hemodinâmica , Interleucina-6/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/microbiologia , Lesão Pulmonar/patologia , Nitratos/sangue , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Nitritos/sangue , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Peroxidase/metabolismo , Pseudomonas aeruginosa/patogenicidade , Distribuição Aleatória , Espécies Reativas de Nitrogênio/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Ovinos , Lesão por Inalação de Fumaça/tratamento farmacológico , Lesão por Inalação de Fumaça/metabolismo , Lesão por Inalação de Fumaça/patologiaRESUMO
OBJECTIVE: Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation. DESIGN: Prospective, randomized, controlled, experimental animals study. SETTING: Investigational intensive care unit at university hospital. SUBJECTS: Adult female sheep. INTERVENTIONS: Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology. CONCLUSIONS: The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Oxazinas/uso terapêutico , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/etiologia , Animais , Queimaduras/complicações , Modelos Animais de Doenças , Feminino , Ovinos , Lesão por Inalação de Fumaça/complicaçõesRESUMO
This article describes the details of our synthetic studies toward the complex marine alkaloid sarain A. Various strategies were conceived, setbacks encountered, and solutions developed, ultimately leading to a successful enantioselective total synthesis. Our route to (+)-sarain A features a number of key steps, including an asymmetric Michael addition to install the C4'-C3'-C7' stereotriad, an enoxysilane-N-sulfonyliminium ion cyclization to set the C3 quaternary carbon stereocenter, and assemble the diazatricycloundecane core, a ring-closing metathesis to construct the 13-membered ring, an intramolecular Stille coupling to fashion the unsaturated 14-membered macrocycle, and a late-stage installation of the tertiary amine-aldehyde proximity interaction.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Alcaloides/síntese química , Alcaloides/química , Alcanos/síntese química , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Ciclização , Modelos Moleculares , Poríferos , EstereoisomerismoRESUMO
The guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde, 1, with an IC(50) of 840 nM against the CCR5 receptor was identified using high-throughput screening. Optimization efforts led to the discovery of a novel piperidine series of CCR5 antagonists. In particular, the 4-hydroxypiperidine derivative, 6k, had improved potency against CCR5, and was a starting point for further optimization. SAR elaboration using parallel synthesis led to the identification of 10h, a potent CCR5 antagonist with an IC(50) of 11 nM.
Assuntos
Antagonistas dos Receptores CCR5 , Química Farmacêutica/métodos , Piperidinas/química , Animais , Linhagem Celular , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fatores de Tempo , TransfecçãoAssuntos
Doença de Alzheimer/patologia , Amiloide/química , Dobramento de Proteína , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Amiloide/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Modelos Químicos , Dados de Sequência Molecular , Estrutura Secundária de Proteína , SolubilidadeRESUMO
Effector functions and proliferation of T helper (Th) cells are influenced by cytokines in the environment. Th1 cells respond to a synergistic effect of interleukin-12 (IL-12) and interleukin-18 (IL-18) to secrete interferon-gamma (IFN-gamma). In contrast, Th2 cells respond to interleukin-4 (IL-4) to secrete IL-4, interleukin-13 (IL-13), interleukin-5 (IL-5), and interleukin-10 (IL-10). The authors were interested in identifying nonpeptide inhibitors of the Th1 response selective for the IL-12/IL-18-mediated secretion of IFN-gamma while leaving the IL-4-mediated Th2 cytokine secretion relatively intact. The authors established a screening protocol using human peripheral blood mononuclear cells (PBMCs) and identified the hydrazino anthranilate compound 1 as a potent inhibitor of IL-12/IL-18-mediated IFN-gamma secretion from CD3(+) cells with an IC(50) around 200 nM. The inhibitor was specific because it had virtually no effect on IL-4-mediated IL-13 release from the same population of cells. Further work established that compound 1 was a potent intracellular iron chelator that inhibited both IL-12/IL-18- and IL-4-mediated T cell proliferation. Iron chelation affects multiple cellular pathways in T cells. Thus, the IL-12/IL-18-mediated proliferation and IFN-gamma secretion are very sensitive to intracellular iron concentration. However, the IL-4-mediated IL-13 secretion does not correlate with proliferation and is partially resistant to potent iron chelation.
Assuntos
Citocinas/metabolismo , Íons/química , Quelantes de Ferro/química , Quelantes de Ferro/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectrometria de Massas , Estrutura Molecular , NF-kappa B/metabolismo , Transcrição Gênica/efeitos dos fármacosAssuntos
Desenho de Fármacos , Genômica/tendências , Proteínas/química , Berlim , Proteínas/metabolismoRESUMO
Fluorinated dihydroquinolines showed reduced basicity of the amidine function. Their syntheses and potencies as neuronal nitric oxide synthase (n-NOS) inhibitors are reported.
Assuntos
Amidinas/metabolismo , Inibidores Enzimáticos/farmacologia , Flúor/química , Óxido Nítrico Sintase/antagonistas & inibidores , Quinolinas/farmacologia , Inibidores Enzimáticos/química , Óxido Nítrico Sintase Tipo I , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.
Assuntos
Benzofuranos/farmacologia , Glucocorticoides/farmacologia , Receptores de Glucocorticoides/agonistas , Ativação Transcricional/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Benzofuranos/administração & dosagem , Benzofuranos/toxicidade , Benzoxazinas , Indução Enzimática/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/toxicidade , Humanos , Técnicas In Vitro , Interleucina-12/biossíntese , Interleucina-8/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ligantes , Camundongos , Prednisolona/administração & dosagem , Prednisolona/farmacologia , Prednisolona/toxicidade , Subunidades Proteicas/biossíntese , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Pele/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Tirosina Transaminase/biossínteseRESUMO
Dihydroquinolines with aminoalkyl side chains have been synthesized and have been shown to be potent n-NOS inhibitors. A marked selectivity versus e-NOS of up to approximately 300-fold was observed, whereas i-NOS was moderately inhibited.
Assuntos
Aminas/química , Óxido Nítrico Sintase/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Quinolinas/síntese química , Proteínas Recombinantes/antagonistas & inibidores , Valores de Referência , Relação Estrutura-AtividadeRESUMO
Dihydroquinolines have been synthesized and have been shown to be potent n-NOS inhibitors. Selectivity versus e-NOS was increased to approximately 100-fold through appropriate substitution at the benzene ring.