RESUMEN
INTRODUCTION: The mechanisms of fluoroquinolone-resistance of Mycoplasma genitalium were analysed by a new method. METHODS: M. genitalium strains from urinary sediments of patients with urethritis were isolated and examined antimicrobial susceptibilities and the mutations in ParC, GyrA and 23S rRNA. Docking models between gyrase and topoisomerase IV with sitafloxacin showed that two binding modes in which the amine moiety at the C-7 position rotated could be constructed. RESULTS: Among 18 strains, 13 strains had mutations with amino-acid changes at Serine 83 in ParC. The MICs of moxifloxacin or sitafloxacin for three strains with only S83I in ParC were 2, 1 and 8 mg/L (moxifloxacin) or 0.13, 0.13 and 1 mg/L (sitafloxacin), respectively. In contrast, the MICs of moxifloxacin or sitafloxacin for 3 strain with S83N in ParC were 0.25, 0.13 and 0.25 mg/L (moxifloxacin) or 0.06, 0.03, and 0,03 mg/L (sitafloxacin), respectively, not significantly different from wild-type isolates. The docking model of sitafloxacin and topoisomerase IV showed that the oxygen atom at the gamma position of Serine 83 of ParC interacted with the sitafloxacin carboxylate moiety. When the S83I substitution occurs, the isoleucine side chain is lipophilic and the residue hydropathy changes from hydrophilicity to hydrophobicity and important H-bond interactions between serine and the carboxylate moiety are lost. When the serine 83 to asparagine substitution (S83N) occurred, the asparagine side chain is hydrophilic and the residue hydropathy does not change. CONCLUSION: The docking model suggests that Ser83 replacements causes attenuation or loss of activity of fluoroquinolones such as sitafloxacin.
Asunto(s)
Infecciones por Mycoplasma , Mycoplasma genitalium , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Girasa de ADN/genética , Topoisomerasa de ADN IV/genética , Farmacorresistencia Bacteriana/genética , Fluoroquinolonas/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Infecciones por Mycoplasma/tratamiento farmacológico , Mycoplasma genitalium/genéticaRESUMEN
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.
Asunto(s)
Amidas/química , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Pirazinas/química , Células 3T3 , Amidas/metabolismo , Amidas/farmacología , Amidas/uso terapéutico , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Solubilidad , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Humanos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Pirrolidinas/farmacocinéticaRESUMEN
We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Triazoles/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Masculino , Ratones , Ratones Obesos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/químicaRESUMEN
Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.
Asunto(s)
Adamantano/análogos & derivados , Descubrimiento de Drogas , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/farmacología , Niacinamida/análogos & derivados , Adamantano/química , Adamantano/farmacocinética , Adamantano/farmacología , Adamantano/uso terapéutico , Administración Oral , Animales , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Humanos , Inhibidores de las Cinasas Janus/farmacocinética , Inhibidores de las Cinasas Janus/uso terapéutico , Ratones , Niacinamida/química , Niacinamida/farmacocinética , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Administración Oral , Animales , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Humanos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Biología Computacional , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP2C19/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Glicina/análogos & derivados , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Espectroscopía de Protones por Resonancia Magnética , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1mg/kg.
Asunto(s)
Acetamidas/farmacología , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Glicina/análogos & derivados , Glicina/farmacología , Acetamidas/síntesis química , Acetamidas/farmacocinética , Animales , Células CHO , Cricetulus , Estabilidad de Medicamentos , Pruebas de Enzimas , Glicina/síntesis química , Glicina/farmacocinética , Humanos , Simulación del Acoplamiento Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Descubrimiento de Drogas , Quinasas Janus/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Pirroles/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Administración Oral , Animales , Disponibilidad Biológica , Permeabilidad de la Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón , Humanos , Quinasas Janus/metabolismo , Masculino , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Piridinas/administración & dosificación , Piridinas/química , Pirroles/administración & dosificación , Pirroles/química , Ratas , Ratas Endogámicas ACI , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.
Asunto(s)
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , 6-Aminonicotinamida/síntesis química , 6-Aminonicotinamida/uso terapéutico , Animales , Rechazo de Injerto/prevención & control , Trasplante de Corazón , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/uso terapéutico , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , RatasRESUMEN
Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Citocromo P-450 CYP3A/metabolismo , Humanos , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Piridinas/química , Piridonas/síntesis química , Piridonas/farmacología , Pirroles/química , Ratas , Ratas Endogámicas Lew , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Relación Estructura-ActividadRESUMEN
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Asunto(s)
Amidas/química , Factores Inmunológicos/síntesis química , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Perros , Rechazo de Injerto/prevención & control , Semivida , Haplorrinos , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Interleucina-2/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Piridinas/química , Ratas , Ratas Endogámicas Lew , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Trasplante HeterotópicoRESUMEN
Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Animales , Proliferación Celular , Inmunomodulación , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Masculino , Informática Médica , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Bazo/citologíaRESUMEN
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro-3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), α(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.
Asunto(s)
Receptor de Serotonina 5-HT2B/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Animales , Células CHO , Cricetulus , Cobayas , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas de la Serotonina/síntesis químicaRESUMEN
Herein, we describe the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives. Among them, the quinuclidin-4-yl thiazolylcarbamate derivative ASP9133 was identified as a promising long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action in a rat model than tiotropium bromide.
Asunto(s)
Carbamatos/farmacología , Quinuclidinas/farmacología , Receptor Muscarínico M3/antagonistas & inhibidores , Animales , Carbamatos/síntesis química , Carbamatos/química , Relación Dosis-Respuesta a Droga , Masculino , Modelos Moleculares , Estructura Molecular , Quinuclidinas/síntesis química , Quinuclidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We previously reported that the novel dual 5-HT2B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT2B and 5-HT7 receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT7), Tyr (Y370:5-HT2B, Y374:5-HT7) and aromatic residue (W131:5-HT2B, F158:5-HT7). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT2B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.
Asunto(s)
Guanidina/análogos & derivados , Receptor de Serotonina 5-HT2B/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Administración Oral , Animales , Sitios de Unión , Temperatura Corporal/efectos de los fármacos , Células CHO , Cricetinae , Cricetulus , Guanidina/síntesis química , Guanidina/farmacocinética , Cobayas , Células HEK293 , Humanos , Hipotermia Inducida , Masculino , Ratones , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Receptor de Serotonina 5-HT2B/genética , Receptor de Serotonina 5-HT2B/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Serotonina/análogos & derivados , Serotonina/farmacología , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacocinética , Relación Estructura-ActividadRESUMEN
Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure-activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50=0.019 µM, rat IC50=0.0051 µM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Tiazoles/química , Tiazoles/farmacología , Amina Oxidasa (conteniendo Cobre)/metabolismo , Aminas/química , Aminas/farmacocinética , Aminas/farmacología , Animales , Moléculas de Adhesión Celular/metabolismo , Diabetes Mellitus Experimental/complicaciones , Retinopatía Diabética/metabolismo , Humanos , Edema Macular/metabolismo , Masculino , Modelos Moleculares , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinéticaRESUMEN
Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high-throughput screening (HTS) of our compound library resulted in the discovery that thiazole derivative 10, which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC(50) of 230 nM; rat IC(50) of 14 nM). Moreover, compound 10 exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Guanidinas/síntesis química , Tiazoles/química , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Sitios de Unión , Moléculas de Adhesión Celular/metabolismo , Complicaciones de la Diabetes , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Guanidinas/farmacocinética , Guanidinas/uso terapéutico , Semivida , Humanos , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Masculino , Simulación del Acoplamiento Molecular , Permeabilidad/efectos de los fármacos , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Tiazoles/uso terapéuticoRESUMEN
Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although our previous compound 1 showed potent VAP-1 inhibitory activity, the activity differed between humans and rats. This issue was overcome by a hybrid design using human VAP-1 specific inhibitor 2, which was found by high-throughput screening (HTS), a docking study of a human VAP-1 homology model, and an analysis of sequence information for humans and rats. As a result, we identified compound 35c, which showed strong VAP-1 inhibitory activity (human IC(50) of 20 nM; rat IC(50) of 72 nM) and significant inhibitory effects in the ex vivo test.