Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Protein Sci ; 33(8): e5110, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39073183

RESUMEN

Inhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS-SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH-1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK-1-89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X-ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.


Asunto(s)
Serina Endopeptidasas , Serina Endopeptidasas/química , Serina Endopeptidasas/metabolismo , Especificidad por Sustrato , Humanos , Diseño de Fármacos , Aminoácidos/química , Aminoácidos/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/metabolismo , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Animales , Factor de Crecimiento de Hepatocito/metabolismo , Factor de Crecimiento de Hepatocito/química , Factor de Crecimiento de Hepatocito/antagonistas & inhibidores
2.
Cell ; 187(16): 4193-4212.e24, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-38942014

RESUMEN

Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in both developmental and disease models, yet brain C1q protein levels increase significantly throughout aging. Here, we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a role of C1q in critical intracellular neuronal processes.


Asunto(s)
Envejecimiento , Encéfalo , Complemento C1q , Homeostasis , Microglía , Neuronas , Ribonucleoproteínas , Animales , Complemento C1q/metabolismo , Ratones , Microglía/metabolismo , Envejecimiento/metabolismo , Encéfalo/metabolismo , Ribonucleoproteínas/metabolismo , Neuronas/metabolismo , Ratones Endogámicos C57BL , Humanos
3.
J Virol ; 98(5): e0190323, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38593045

RESUMEN

We developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases, including transmembrane protease serine 2 (TMPRSS2), matriptase, and hepsin. TMPRSS2 is a membrane-associated protease that is highly expressed in the upper and lower respiratory tracts and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell entry, replication, and dissemination of new virus particles. We have previously shown that compound MM3122 exhibited subnanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Furthermore, we evaluated MM3122 in a mouse model of COVID-19 and demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in proinflammatory cytokine and chemokine production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2-infected mice. Therefore, MM3122 is a promising lead candidate small-molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses. IMPORTANCE: SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and a therapeutic drug for the treatment of COVID-19 given intraperitoneally in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research, but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.


Asunto(s)
Antivirales , Benzotiazoles , Tratamiento Farmacológico de COVID-19 , Oligopéptidos , SARS-CoV-2 , Inhibidores de Serina Proteinasa , Replicación Viral , Animales , Femenino , Humanos , Ratones , Antivirales/farmacología , Chlorocebus aethiops , COVID-19/virología , Modelos Animales de Enfermedad , Pulmón/virología , Pulmón/patología , Pulmón/efectos de los fármacos , Peptidomiméticos/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Inhibidores de Serina Proteinasa/uso terapéutico , Células Vero , Replicación Viral/efectos de los fármacos , Oligopéptidos/farmacología , Benzotiazoles/farmacología
4.
bioRxiv ; 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38405752

RESUMEN

We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease serine 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly expressed in the upper and lower respiratory tract and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell receptor binding, entry, replication, and dissemination of new virion particles. We have previously shown that compound MM3122 exhibited sub nanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell-viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Further, we have evaluated MM3122 in a mouse model of COVID-19 and have demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion, and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in pro-inflammatory cytokines and chemokines production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2 infected mice. Therefore, MM3122 is a promising lead candidate small molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses. IMPORTANCE: SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host-cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and therapeutic drug for the treatment of COVID-19 in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.

7.
Paediatr Child Health ; 28(6): 333-335, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37744758
8.
Children (Basel) ; 10(5)2023 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-37238356

RESUMEN

Conjunctivitis is a common pediatric problem and is broadly divided into infectious and non-infectious etiologies. Bacterial conjunctivitis makes up the majority of cases in children and often presents with purulent discharge and mattering of the eyelids. Treatment is supportive with an individual approach to antibiotic use in uncomplicated cases since it may shorten symptom duration, but is not without risks. Viral conjunctivitis is the other infectious cause and is primarily caused by adenovirus, with a burning, gritty feeling and watery discharge. Treatment is supportive. Allergic conjunctivitis is largely seasonal and presents with bilateral itching and watery discharge. Treatment can include topical lubricants, topical antihistamine agents, or systemic antihistamines. Other causes of conjunctivitis include foreign bodies and non-allergic environmental causes. Contact lens wearers should always be treated for bacterial conjunctivitis and referred to evaluate for corneal ulcers. Neonatal conjunctivitis requires special care with unique pathogens and considerations. This review covers essential information for the primary care pediatric provider as they assess cases of conjunctivitis.

9.
J Med Syst ; 46(8): 57, 2022 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-35819553

RESUMEN

The American healthcare system has become one of the world's most complex for both patients and healthcare providers to navigate, particularly in regards to health insurance. This editorial piece further explores the problems that complexities in health insurance create, and several solution proposals to provide patients with educational resources concerning this important topic, in theory, leading to better decision-making in regards to health insurance.


Asunto(s)
Alfabetización en Salud , Seguro de Salud , Atención a la Salud , Humanos , Estados Unidos
10.
PLOS Glob Public Health ; 2(6): e0000215, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36962313

RESUMEN

A community engaged passive surveillance program was utilized to acquire ticks and associated information throughout New York state. Ticks were speciated and screened for several tick-borne pathogens. Of these ticks, only I. scapularis was commonly infected with pathogens of human relevance, including B. burgdorferi, B. miyamotoi, A. phagocytophilum, B. microti, and Powassan virus. In addition, the geographic and temporal distribution of tick species and pathogens was determined. This enabled the construction of a powerful visual analytical mapping tool, tickMAP to track the emergence of ticks and tick-borne pathogens in real-time. The public can use this tool to identify hot-spots of disease emergence, clinicians for supportive evidence during differential diagnosis, and researchers to better understand factors influencing the emergence of ticks and tick-borne diseases in New York. Overall, we have created a community-engaged tick surveillance program and an interactive visual analytical tickMAP that other regions could emulate to provide real-time tracking and an early warning for the emergence of tick-borne diseases.

11.
J Med Chem ; 64(24): 18158-18174, 2021 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-34902246

RESUMEN

Hepatocyte growth factor (HGF), the ligand for the MET receptor tyrosine kinase, is a tumor-promoting factor that is abundant in the tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more of the serine endopeptidases matriptase, hepsin, and HGF activator is the rate-limiting step in HGF/MET signaling. Herein, we have rationally designed a novel class of side chain cyclized macrocyclic peptide inhibitors. The new series of cyclic tripeptides has superior metabolic stability and significantly improved pharmacokinetics in mice relative to the corresponding linear peptides. We identified the lead compound VD2173 that potently inhibits matriptase and hepsin, which was tested in parallel alongside the acyclic inhibitor ZFH7116 using both in vitro and in vivo models of lung cancer. We demonstrated that both compounds block pro-HGF activation, abrogate HGF-mediated wound healing, and overcome resistance to EGFR- and MET-targeted therapy in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent growth of lung cancer tumors in mice.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Factor de Crecimiento de Hepatocito/metabolismo , Neoplasias Pulmonares/patología , Compuestos Macrocíclicos/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Progresión de la Enfermedad , Descubrimiento de Drogas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/uso terapéutico , Ratones , Inhibidores de Serina Proteinasa/sangre , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/uso terapéutico , Relación Estructura-Actividad
12.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-34635581

RESUMEN

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.


Asunto(s)
Benzotiazoles/farmacología , Tratamiento Farmacológico de COVID-19 , Oligopéptidos/farmacología , SARS-CoV-2/efectos de los fármacos , Serina Endopeptidasas/genética , Animales , Benzamidinas/química , Benzotiazoles/farmacocinética , COVID-19/genética , COVID-19/virología , Línea Celular , Diseño de Fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Ésteres/química , Guanidinas/química , Humanos , Pulmón/efectos de los fármacos , Pulmón/virología , Ratones , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Oligopéptidos/farmacocinética , SARS-CoV-2/patogenicidad , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/ultraestructura , Bibliotecas de Moléculas Pequeñas/farmacología , Especificidad por Sustrato/efectos de los fármacos , Internalización del Virus/efectos de los fármacos
13.
Cureus ; 13(5): e15076, 2021 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-34150410

RESUMEN

Pyogenic granulomas represent benign vascular tumors that can present on the skin and mucous membranes. Multiple etiologic agents have been implicated in the pathogenesis including several systemic medications. Two notable oncologic therapies, epidermal growth factor receptor inhibitors and vascular endothelial growth factor receptor inhibitors, have each been associated with drug-induced pyogenic granulomas. We report a novel case report of dual therapy, medication-induced pyogenic granulomas. This likely represents a synergistic relationship between an epidermal growth factor receptor inhibitor, osimertinib, and a vascular endothelial growth factor receptor inhibitor, ramucirumab.

14.
bioRxiv ; 2021 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-34131661

RESUMEN

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered a novel class of small molecule ketobenzothiazole TMPRSS2 inhibitors with significantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 ( 4 ) has an IC 50 of 340 pM against recombinant full-length TMPRSS2 protein, an EC 50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 chimeric virus, and an EC 50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV) cell entry with an EC 50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

15.
Pathogens ; 10(1)2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33466870

RESUMEN

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 µM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.

16.
EMBO J ; 39(16): e105380, 2020 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-32657463

RESUMEN

Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.


Asunto(s)
Hipocampo/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Fosfatidilserinas/metabolismo , Sinapsis/metabolismo , Animales , Técnicas de Cocultivo , Complemento C1q/genética , Complemento C1q/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Fosfatidilserinas/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Sinapsis/genética
17.
AIDS ; 34(7): 979-988, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32073448

RESUMEN

OBJECTIVE: Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. DESIGN: Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. METHODS: First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. RESULTS: PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. CONCLUSION: Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.


Asunto(s)
Encéfalo/metabolismo , Proteína gp120 de Envoltorio del VIH/toxicidad , Infecciones por VIH/complicaciones , Proteínas Asociadas a Microtúbulos/líquido cefalorraquídeo , Neuronas/metabolismo , Péptidos/farmacología , Adulto , Animales , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos , Trastornos Neurocognitivos , Ratas
18.
PLoS One ; 8(3): e59190, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23533605

RESUMEN

Storage and transmission of the data produced by modern DNA sequencing instruments has become a major concern, which prompted the Pistoia Alliance to pose the SequenceSqueeze contest for compression of FASTQ files. We present several compression entries from the competition, Fastqz and Samcomp/Fqzcomp, including the winning entry. These are compared against existing algorithms for both reference based compression (CRAM, Goby) and non-reference based compression (DSRC, BAM) and other recently published competition entries (Quip, SCALCE). The tools are shown to be the new Pareto frontier for FASTQ compression, offering state of the art ratios at affordable CPU costs. All programs are freely available on SourceForge. Fastqz: https://sourceforge.net/projects/fastqz/, fqzcomp: https://sourceforge.net/projects/fqzcomp/, and samcomp: https://sourceforge.net/projects/samcomp/.


Asunto(s)
Biología Computacional/métodos , Compresión de Datos/métodos , Análisis de Secuencia de ADN/métodos , Programas Informáticos
20.
J Med Chem ; 53(16): 5979-6002, 2010 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-20672822

RESUMEN

We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.


Asunto(s)
Antihipertensivos/síntesis química , Hipertensión/tratamiento farmacológico , Indazoles/síntesis química , Enfermedades Renales/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides , Nitrilos/síntesis química , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Línea Celular Tumoral , Clorobencenos , Cristalografía por Rayos X , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indenos , Masculino , Modelos Moleculares , Conformación Molecular , Nitrilos/farmacocinética , Nitrilos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...