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2.
Arch Pharm (Weinheim) ; 342(12): 740-7, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19921682

RESUMEN

Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.


Asunto(s)
Carbolinas/síntesis química , Carbolinas/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Receptores de Serotonina/efectos de los fármacos , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Indoles/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad
3.
J Biomol Screen ; 11(6): 694-703, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16844966

RESUMEN

When studying cysteinyl proteases in general and caspases in particular, it is generally accepted that a reaction buffer must contain a reducing agent to prevent essential cysteinyl groups from spontaneous oxidation. Dithiothreitol (DTT) and beta-mercaptoethanol (beta-MCE) are 2 of the most broadly used reducing agents. While screening a library of small molecules against caspase-3, the authors have found that the nature of the reducing agent used, DTT or beta-MCE, dramatically affects screening results and leads to identification of nonoverlapping hits. Screening in DTT-containing buffer revealed few novel classes of small molecules that selectively and reversibly inhibit caspase-3 but failed to identify isatin sulfonamides recently found to be potent and selective caspase-3 inhibitors (false negatives). On the other hand, screening in the presence of beta-MCE failed to identify a series of hit compounds, 1,3-dioxo-2,3-dichloro-1H-pyrrolo[3,4-c]quinolines, discovered with DTT, whereas isatin sulphonamides in these conditions exhibited strong caspase-3 inhibition. In this work, the authors show that thiol-containing reducing agents can affect catalytic activity of caspase-3 and modify its thermostability in a redox-potential-independent manner. The authors speculate that the differential structural modifications of caspase-3 seen with different reducing agents represent structurally different caspase-3 conformations and are responsible for its differential sensitivity to small molecules of different chemotypes. Hence, selection of the reducing agent may dramatically affect the quality of high-throughput screening campaigns.


Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/análisis , Caspasa 3 , Inhibidores de Cisteína Proteinasa/farmacología , Ditiotreitol/metabolismo , Mercaptoetanol/metabolismo , Relación Estructura-Actividad
4.
J Biomol Screen ; 11(3): 277-85, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16490769

RESUMEN

From the authors' 650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and anti-apoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC (50)=130 nM), was reversible though noncompetitive, and had a broad selectivity profile to other caspases belonging to groups I to III. The compound was effective in preventing staurosporine induced apoptosis in a few cell lines and retinoic acid-induced apoptosis in zebrafish.


Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3 , Línea Celular , Inhibidores de Cisteína Proteinasa/química , Humanos , Ratones , Quinolinas/química , Quinolinas/farmacología , Pez Cebra
5.
J Med Chem ; 58(17): 6875-98, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26222319

RESUMEN

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.


Asunto(s)
Antineoplásicos/química , Isoindoles/química , Piperidinas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoindoles/administración & dosificación , Isoindoles/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temozolomida , Neoplasias de la Mama Triple Negativas
6.
Nat Med ; 21(2): 159-65, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25559344

RESUMEN

The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Derivados del Benceno/farmacología , Ácidos y Sales Biliares/metabolismo , Factores de Crecimiento de Fibroblastos/efectos de los fármacos , Resistencia a la Insulina , Mucosa Intestinal/metabolismo , Obesidad/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Aumento de Peso/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Técnica de Clampeo de la Glucosa , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo
7.
PLoS One ; 6(6): e19904, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21698280

RESUMEN

BACKGROUND: Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. PRINCIPAL FINDINGS: Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. SIGNIFICANCE: We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists.


Asunto(s)
Adenocarcinoma/patología , Antineoplásicos/farmacología , Benzamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Modelos Animales de Enfermedad , Neoplasias Pancreáticas/patología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Adenocarcinoma/metabolismo , Animales , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , División Celular/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Ratones , Neoplasias Pancreáticas/metabolismo , Transducción de Señal , Receptor Smoothened , Trasplante Heterólogo
8.
J Comb Chem ; 8(4): 469-79, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16827558

RESUMEN

In this work, we explored several original combinatorial derivatization patterns for the 3,4-dihydro-2H-1,4-benzothiazine scaffold. The synthesis begins with commercially available 4-chloro- and 4-fluoro-3-nitrobenzoates and employs a sequence of moderate and high-yielding reactions that display a relatively high substituent tolerance. Simple manual techniques for parallel reactions were coupled with easy workup and purification procedures to give high-purity final products. The developed approach was easily adaptable for parallel synthesis of more than 2600 novel 2H-benzo[1,4]thiazine-6-carboxylic acid amides, which were efficiently prepared in a semiautomatic fashion using special CombiSyn synthesizers.


Asunto(s)
Cromatografía Liquida/métodos , Técnicas Químicas Combinatorias , Tiazinas/síntesis química , Diseño de Fármacos , Estructura Molecular
9.
J Comb Chem ; 7(2): 227-35, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15762750

RESUMEN

Two efficient strategies for solution-phase parallel synthesis of libraries of quinoline derivatives are described. The first synthetic pathway features the Pfitzinger reaction of isatin with diethyl malonate and sulfochlorination of the resulting 2-oxo-1,2-dihydroquinoline-4-carboxylate followed by generation of sulfonamide library. The second strategy employs the unusual behavior of 5-sulfamoylisatins in Pfitzinger reactions, which results in formation of 6-sulfamoyl-4-carboxyquinolines instead of the anticipated 2-oxo-1,2-dihydroquinoline structures. The obtained carboxylates appeared to be convenient synthetic intermediates for the generation of the corresponding carboxamide libraries. Using these reagents, the parallel solution-phase synthesis of more than 500 substituted quinoline and 2-oxo-1,2-dihydroquinoline derivatives has been accomplished on the 50-100-mg scale. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures to give high-purity final products. The scope and limitations of the developed approaches are discussed.


Asunto(s)
Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Quinolinas/síntesis química , Sulfonamidas/síntesis química , Estructura Molecular , Quinolinas/química , Sulfonamidas/química
10.
J Comb Chem ; 6(5): 828-34, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15360220

RESUMEN

The parallel solution-phase synthesis of a series of building blocks and combinatorial libraries based on natural bispidine scaffold has been accomplished. Key reactions include catalytic hydrogenation of the (-)-cytisine heterocyclic system, followed by alkali-mediated ring cleavage. Using this approach, a series of new bispidine core building blocks for combinatorial synthesis with three points of diversity were effectively synthesized. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation reactions. Obtained combinatorial libraries of 3,4,7-trisubstituted bispidines are potentially useful in the discovery of novel physiologically active compounds.

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