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1.
Nat Commun ; 6: 7645, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26134520

RESUMEN

SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.


Asunto(s)
Lisina/metabolismo , Sirtuina 1/química , Secuencia de Aminoácidos , Sitios de Unión/genética , Dominio Catalítico/genética , Cristalización , Cristalografía por Rayos X , Medición de Intercambio de Deuterio , Escherichia coli , Vectores Genéticos , Humanos , Espectrometría de Masas , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica , Sirtuina 1/genética , Sirtuina 1/metabolismo , Transfección
2.
J Med Chem ; 56(9): 3666-79, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23570514

RESUMEN

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.


Asunto(s)
Descubrimiento de Drogas , Pirimidinas/química , Pirimidinas/farmacología , Sirtuinas/antagonistas & inhibidores , Humanos , Modelos Moleculares , Conformación Proteica , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/química , Sirtuina 2/antagonistas & inhibidores , Sirtuina 2/química , Sirtuina 3/antagonistas & inhibidores , Sirtuina 3/química , Sirtuinas/química
3.
Science ; 339(6124): 1216-9, 2013 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-23471411

RESUMEN

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.


Asunto(s)
Sirtuina 1/química , Sirtuina 1/metabolismo , Estilbenos/farmacología , Regulación Alostérica , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Células Cultivadas , Activación Enzimática , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/genética , Ácido Glutámico/química , Ácido Glutámico/genética , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Datos de Secuencia Molecular , Mioblastos/efectos de los fármacos , Mioblastos/enzimología , Estructura Terciaria de Proteína , Resveratrol , Sirtuina 1/genética , Estilbenos/química , Especificidad por Sustrato
4.
Bioorg Med Chem Lett ; 21(9): 2641-5, 2011 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-21295475

RESUMEN

A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.


Asunto(s)
Descubrimiento de Drogas , Ingestión de Alimentos/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Depresores del Apetito/farmacología , Presión Sanguínea/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazolonas/síntesis química , Pirazolonas/química , Pirazolonas/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Ratas , Ratas Sprague-Dawley
6.
Bioorg Med Chem Lett ; 20(15): 4359-63, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20615696

RESUMEN

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.


Asunto(s)
Pirazinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Perros , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Macaca mulatta , Microsomas Hepáticos/metabolismo , Naftiridinas/síntesis química , Naftiridinas/química , Dolor/tratamiento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Ratas , Canales Catiónicos TRPV/metabolismo
7.
J Med Chem ; 53(8): 3330-48, 2010 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-20307063

RESUMEN

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.


Asunto(s)
Analgésicos/síntesis química , Naftiridinas/síntesis química , Pirazinas/síntesis química , Piridinas/síntesis química , Pirimidinas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Células COS , Capsaicina/farmacología , Chlorocebus aethiops , Calor , Humanos , Hiperalgesia/tratamiento farmacológico , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Microsomas Hepáticos , Naftiridinas/química , Naftiridinas/farmacología , Dolor/tratamiento farmacológico , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Quinolinas/síntesis química , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/agonistas
9.
Nat Rev Drug Discov ; 6(5): 357-72, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17464295

RESUMEN

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.


Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/genética , Analgésicos/uso terapéutico , Animales , Clonación Molecular , Glucosa/metabolismo , Humanos , Enfermedades Musculares/tratamiento farmacológico , Enfermedades de la Piel/tratamiento farmacológico , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/fisiología , Enfermedades Urológicas/tratamiento farmacológico
11.
J Med Chem ; 47(9): 2318-25, 2004 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-15084130

RESUMEN

Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4-diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-[4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K(i) = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 microM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.


Asunto(s)
Amidas/síntesis química , Ciclohexanos/síntesis química , Imidazoles/síntesis química , Receptores de Neuropéptido Y/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/farmacología , Animales , Línea Celular , Ciclohexanos/farmacocinética , Ciclohexanos/farmacología , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/fisiología , Relación Estructura-Actividad
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