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1.
Int J Cancer ; 140(2): 449-459, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27699769

RESUMEN

The PI3K-AKT-mTOR signaling cascade is activated in the majority of human cancers, and its activation also plays a key role in resistance to chemo and targeted therapeutics. In particular, in both breast and prostate cancer, increased AKT pathway activity is associated with cancer progression, treatment resistance and poor disease outcome. Here, we evaluated the activity of a novel allosteric AKT1/2 inhibitor, BAY 1125976, in biochemical, cellular mechanistic, functional and in vivo efficacy studies in a variety of tumor models. In in vitro kinase activity assays, BAY 1125976 potently and selectively inhibited the activity of full-length AKT1 and AKT2 by binding into an allosteric binding pocket formed by kinase and PH domain. In accordance with this proposed allosteric binding mode, BAY 1125976 bound to inactive AKT1 and inhibited T308 phosphorylation by PDK1, while the activity of truncated AKT proteins lacking the pleckstrin homology domain was not inhibited. In vitro, BAY 1125976 inhibited cell proliferation in a broad panel of human cancer cell lines. Particularly high activity was observed in breast and prostate cancer cell lines expressing estrogen or androgen receptors. Furthermore, BAY 1125976 exhibited strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CAH1074R mutant), the MCF7 and HBCx-2 breast cancer models and the AKTE17K mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models. These findings indicate that BAY 1125976 is a potent and highly selective allosteric AKT1/2 inhibitor that targets tumors displaying PI3K/AKT/mTOR pathway activation, providing opportunities for the clinical development of new, effective treatments.


Asunto(s)
Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sulfonas/farmacología , Animales , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Células HeLa , Humanos , Células MCF-7 , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
2.
J Cardiovasc Pharmacol ; 64(1): 69-78, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24621652

RESUMEN

Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.


Asunto(s)
Insuficiencia Cardíaca/prevención & control , Enfermedades Renales/prevención & control , Antagonistas de Receptores de Mineralocorticoides/farmacología , Naftiridinas/farmacología , Espironolactona/análogos & derivados , Animales , Autorradiografía , Cardiomegalia/prevención & control , Modelos Animales de Enfermedad , Eplerenona , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Naftiridinas/farmacocinética , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Espironolactona/farmacocinética , Espironolactona/farmacología , Distribución Tisular
3.
J Biol Chem ; 285(39): 29932-40, 2010 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-20650892

RESUMEN

Limitations of current steroidal mineralocorticoid receptor (MR) antagonists have stimulated the search for a new generation of molecules. We screened for novel nonsteroidal compounds and identified MR antagonists derived from the chemical class of dihydropyridines. Chemical optimization resulted in BR-4628, which displays high in vitro and in vivo MR potency as well as selectivity with respect to the other steroid hormone receptors and the L-type calcium channel. Biochemical studies demonstrated that BR-4628 forms complexes with MR that do not promote the recruitment of transcriptional co-regulators. Docking experiments, using the crystal structure of the MR ligand-binding domain in an agonist conformation, revealed that BR-4628 accommodates in the MR ligand-binding cavity differently in comparison with the classical steroidal MR antagonists. An alanine scanning mutagenesis approach, based on BR-4628 docking, allowed identifying its anchoring mode within the ligand-binding cavity. Altogether, we propose that BR-4628 is a bulky antagonist that inactivates MR through a passive mechanism. It represents the prototype of a new class of MR antagonists.


Asunto(s)
Dihidropiridinas/farmacología , Antagonistas de Receptores de Mineralocorticoides , Sustitución de Aminoácidos , Animales , Sitios de Unión , Células CHO , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Cricetinae , Cricetulus , Cristalografía por Rayos X , Dihidropiridinas/química , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Mutación Missense , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo
5.
Neuropharmacology ; 55(5): 908-18, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18674549

RESUMEN

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 microM, but not 30 microM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.


Asunto(s)
Reacción de Prevención/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Reconocimiento Visual de Modelos/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Antagonistas Colinérgicos/farmacología , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica , Inhibidores Enzimáticos/química , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Hipocampo/efectos de la radiación , Técnicas In Vitro , Potenciación a Largo Plazo/fisiología , Potenciación a Largo Plazo/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Pirazoles/química , Pirimidinas/química , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Escopolamina/farmacología
6.
J Endocrinol ; 234(1): T125-T140, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28634268

RESUMEN

The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.


Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/farmacología , Receptores de Mineralocorticoides/metabolismo , Investigación/historia , Animales , Regulación de la Expresión Génica/fisiología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Antagonistas de Receptores de Mineralocorticoides/química , Receptores de Mineralocorticoides/genética
7.
ChemMedChem ; 10(7): 1163-73, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26083237

RESUMEN

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.


Asunto(s)
Congelación , Elastasa de Leucocito/antagonistas & inhibidores , Enfermedades Pulmonares/enzimología , Proteínas Inhibidoras de Proteinasas Secretoras/farmacología , Pirimidinonas/farmacología , Sulfonas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Elastasa de Leucocito/metabolismo , Conformación Molecular , Proteínas Inhibidoras de Proteinasas Secretoras/química , Pirimidinonas/química , Relación Estructura-Actividad , Sulfonas/química
8.
ChemMedChem ; 7(8): 1385-403, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22791416

RESUMEN

Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.


Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/química , Naftiridinas/química , Receptores de Mineralocorticoides/química , Animales , Sitios de Unión , Enfermedad Crónica , Simulación por Computador , Evaluación Preclínica de Medicamentos , Insuficiencia Cardíaca/complicaciones , Humanos , Enfermedades Renales/complicaciones , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/síntesis química , Naftiridinas/uso terapéutico , Potasio/orina , Estructura Terciaria de Proteína , Ratas , Receptores de Mineralocorticoides/metabolismo , Sodio/orina
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