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1.
Peptides ; 152: 170760, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35150805

RESUMEN

A new strategy of peptide half-life extension has been evaluated. We investigated libraries of a small and very stable protein scaffold called Nanofitin, capable of high affinity for protein targets. We have identified Nanofitins targeting Human and mouse Serum Albumin, which could significantly improve the pharmacokinetics of an active associated peptide, mobilizing the patient's own albumin without external source. To demonstrate the impact of this approach on half-life extension, a genetic fusion of an Exenatide peptide with an Albumin Binding Nanofitin (ABNF) was performed. Specific activity of Exenatide-ABNF was measured and unaffected by the fusion. In vivo mice results provided convincing data (t½ of 8 min for Exenatide peptide compared to 20 h for Exenatide-ABNF) with sustained pharmacological activity over 3 days. This study constitutes a proof-of-concept of in vivo half-life extension of a biologic using an ABNF. Besides, the absence of cysteine in the Nanofitin scaffold, which is therefore devoid of structuring disulfide bonds, allows manufacturing in microbial cost effective systems.


Asunto(s)
Productos Biológicos , Péptidos , Albúminas , Animales , Exenatida , Semivida , Ratones , Péptidos/química
2.
Sci Rep ; 5: 7642, 2015 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-25560837

RESUMEN

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.


Asunto(s)
Analgésicos/farmacología , Ácidos Araquidónicos/metabolismo , Carbamatos/farmacología , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Aprendizaje/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Monoacilglicerol Lipasas/metabolismo , Sulfonamidas/farmacología , Acetilcolina/metabolismo , Administración Oral , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Ácidos Araquidónicos/química , Sitios de Unión , Encéfalo/metabolismo , Antagonistas de Receptores de Cannabinoides/farmacología , Carbamatos/química , Carbamatos/uso terapéutico , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Estimulación Eléctrica , Endocannabinoides/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glicéridos/química , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Hidrólisis , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Monoacilglicerol Lipasas/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Dolor/patología , Piperidinas/farmacología , Estructura Terciaria de Proteína , Pirazoles/farmacología , Rimonabant , Convulsiones/tratamiento farmacológico , Convulsiones/patología , Sulfonamidas/química , Sulfonamidas/uso terapéutico
3.
J Med Chem ; 58(1): 376-400, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-25402320

RESUMEN

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.


Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Pirimidinonas/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Células CACO-2 , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas Clase III/química , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Masculino , Ratones SCID , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Neoplasias/patología , Unión Proteica , Estructura Terciaria de Proteína , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratas Sprague-Dawley , Homología de Secuencia de Aminoácido , Termodinámica , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Med Chem ; 57(3): 903-20, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24387221

RESUMEN

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.


Asunto(s)
Antineoplásicos/química , Indoles/química , Neoplasias/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinonas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Humanos , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Microsomas Hepáticos/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular , Trasplante de Neoplasias , Neoplasias/enzimología , Fosfohidrolasa PTEN/genética , Unión Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Ratas Desnudas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 22(20): 6381-4, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-22981333

RESUMEN

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Pirimidinonas/química , Pirimidinonas/farmacología , Anilidas/química , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Cristalografía por Rayos X , Femenino , Eliminación de Gen , Humanos , Masculino , Ratones , Ratones SCID , Modelos Moleculares , Fosfohidrolasa PTEN/genética , Próstata/citología , Próstata/efectos de los fármacos , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Pirimidinonas/farmacocinética , Relación Estructura-Actividad
6.
J Med Chem ; 55(10): 4788-805, 2012 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-22524426

RESUMEN

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kß has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kß-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kß and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kß isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.


Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Benzoxazoles/síntesis química , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Pirimidinonas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Humanos , Isoenzimas/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/patología , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
7.
ChemMedChem ; 6(4): 633-53, 2011 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-21400663

RESUMEN

Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC50 values of 1.6 and 336 nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.


Asunto(s)
PPAR delta/agonistas , PPAR gamma/agonistas , Sulfonas/uso terapéutico , Tiadiazoles/uso terapéutico , Animales , Sitios de Unión , Cristalografía por Rayos X , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ratones , PPAR delta/metabolismo , PPAR gamma/metabolismo , Relación Estructura-Actividad , Sulfonas/agonistas , Sulfonas/síntesis química , Sulfonas/química , Tiadiazoles/agonistas , Tiadiazoles/síntesis química , Tiadiazoles/química
8.
FEBS J ; 272(16): 4023-33, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16098186

RESUMEN

Parkinson's disease is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway accompanied by the presence of intracellular cytoplasmic inclusions, termed Lewy bodies. Fibrillized alpha-synuclein forms the major component of Lewy bodies. We reported a specific interaction between rat alpha-synuclein and tat binding protein 1, a subunit of PA700, the regulatory complex of the 26S proteasome. It has been demonstrated that PA700 prevents the aggregation of misfolded, nonubiquinated substrates. In this study, we examine the effect of PA700 on the aggregation of wild-type and A53T mutant alpha-synuclein. PA700 inhibits both wild-type and A53T alpha-synuclein fibril formation as measured by Thioflavin T fluorescence. Using size exclusion chromatography, we present evidence for a stable PA700-alpha-synuclein complex. Sedimentation analyses reveal that PA700 sequesters alpha-synuclein in an assembly incompetent form. Analysis of the morphology of wild-type and A53T alpha-synuclein aggregates during the course of fibrillization by electron microscopy demonstrate the formation of amyloid-like fibrils. Secondary structure analyses of wild-type and A53T alpha-synuclein assembled in the presence of PA700 revealed a decrease in the overall amount of assembled alpha-synuclein with no significant change in protein conformation. Thus, PA700 acts on alpha-synuclein assembly and not on the structure of fibrils. We hypothesize that PA700 sequesters alpha-synuclein oligomeric species that are the precursors of the fibrillar form of the protein, thus preventing its assembly into fibrils.


Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Biopolímeros , Cromatografía en Gel , Electroforesis en Gel de Poliacrilamida , Cinética , Microscopía Electrónica de Transmisión , Proteínas del Tejido Nervioso/química , Pliegue de Proteína , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Sinucleínas , alfa-Sinucleína
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