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1.
Bioorg Med Chem Lett ; 28(10): 1958-1963, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29653895

RESUMEN

Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake.


Asunto(s)
Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/farmacología , Enlace de Hidrógeno , Indoles/química , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Mutagénesis , Inhibidores de Proteínas Quinasas/metabolismo
2.
Am J Physiol Endocrinol Metab ; 310(6): E405-17, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26714847

RESUMEN

Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167-201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated (r(2) = 0.90-0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM.


Asunto(s)
Andrógenos/farmacología , Proteínas Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Proteoma/efectos de los fármacos , Animales , Composición Corporal , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Forma MM de la Creatina-Quinasa/metabolismo , Deuterio , Femenino , Espectrometría de Masas , Proteínas Musculares/biosíntesis , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Tamaño de los Órganos , Ovariectomía , Proteoma/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo
3.
J Pharmacol Exp Ther ; 339(1): 24-34, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21712426

RESUMEN

µ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with µ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.


Asunto(s)
Fármacos Antiobesidad/farmacología , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Indanos/farmacología , Receptores Opioides mu/agonistas , Triazoles/farmacología , Adiposidad/efectos de los fármacos , Animales , Fármacos Antiobesidad/farmacocinética , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Calibración , Condicionamiento Operante/efectos de los fármacos , Interpretación Estadística de Datos , Preferencias Alimentarias/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Indanos/farmacocinética , Inyecciones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Respuesta de Saciedad/efectos de los fármacos , Triazoles/farmacocinética , Pérdida de Peso/efectos de los fármacos
4.
Drug Metab Dispos ; 36(2): 380-5, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18006651

RESUMEN

Phenoxypropoxybiguanides, such as PS-15, are antimalarial prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, WR99210, the active metabolite of PS-15, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Recently, in vitro metabolism of a new series of phenoxypropoxybiguanide analogs has examined the production of the active triazine metabolites by human liver microsomes. The purpose of this investigation was to elucidate the primary cytochrome P450 isoforms involved in the production of active metabolites in the current lead candidate. By using expressed human recombinant isoform preparations, specific chemical inhibitors, and isoform-specific inhibitory antibodies, the primary cytochrome P450 isoforms involved in the in vitro metabolic activation of JPC-2056 were elucidated. Unlike proguanil, which is metabolized primarily by CYP2C19, the results indicate that CYP3A4 plays a more important role in the metabolism of both PS-15 and JPC-2056. Whereas CYP2D6 appears to play a major role in the metabolism of PS-15 to WR99210, it appears less important in the conversion of JPC-2056 to JPC-2067. These results are encouraging, considering the prominence of CYP2C19 and CYP2D6 polymorphisms in certain populations at risk for contracting malaria, because the current clinical prodrug candidate from this series may be less dependent on these enzymes for metabolic activation.


Asunto(s)
Antimaláricos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Profármacos/metabolismo , Proguanil/análogos & derivados , Proguanil/metabolismo , Anticuerpos Monoclonales/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Humanos , Microsomas Hepáticos/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/metabolismo , Triazinas/metabolismo
5.
J Med Chem ; 48(8): 2805-13, 2005 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-15828818

RESUMEN

Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC(50) values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V(max) for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K(m) ranging from 44.8 to 221 microM. The results of these studies will be used to guide the selection of a lead candidate.


Asunto(s)
Antimaláricos/farmacocinética , Biguanidas/farmacocinética , Microsomas Hepáticos/metabolismo , Profármacos/farmacocinética , Triazinas/metabolismo , Animales , Antimaláricos/química , Antimaláricos/metabolismo , Biguanidas/química , Biguanidas/metabolismo , Cromatografía Liquida , Resistencia a Medicamentos , Antagonistas del Ácido Fólico/farmacología , Humanos , Técnicas In Vitro , Espectrometría de Masas , Plasmodium falciparum/efectos de los fármacos , Profármacos/química , Profármacos/metabolismo , Relación Estructura-Actividad
6.
Comb Chem High Throughput Screen ; 8(1): 89-98, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15720200

RESUMEN

The high level of attrition of drugs in clinical development has led pharmaceutical companies to increase the efficiency of their lead identification and development through techniques such as combinatorial chemistry and high-throughput (HTP) screening. Since the major reasons for clinical drug candidate failure other than efficacy are pharmacokinetics and toxicity, attention has been focused on assessing properties such as metabolic stability, drug-drug interactions (DDI), and absorption earlier in the drug discovery process. Animal studies are simply too labor-intensive and expensive to use for evaluating every hit, so it has been necessary to develop and implement higher throughput in vitro ADME screens to manage the large number of compounds of interest. The antimalarial drug development program at the Walter Reed Army Institute of Research, Division of Experimental Therapeutics (WRAIR/ET) has adopted this paradigm in its search for a long-term prophylactic for the prevention of malaria. The overarching goal of this program is to develop new, long half-life, orally bioavailable compounds with potent intrinsic activity against liver- and blood-stage parasites. From the WRAIR HTP antimalarial screen, numerous compounds are regularly identified with potent activity. These hits are now immediately evaluated using a panel of in vitro ADME screens to identify and predict compounds that will meet our specific treatment criteria. In this review, the WRAIR ADME screening program for antimalarial drugs is described as well as how we have implemented it to predict the ADME properties of small molecule for the identification of promising drug candidates.


Asunto(s)
Antimaláricos/química , Animales , Antimaláricos/farmacología , Línea Celular , Perros , Diseño de Fármacos , Interacciones Farmacológicas , Humanos , Absorción Intestinal , Espectrometría de Masas
7.
J Med Chem ; 58(17): 7021-56, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26267483

RESUMEN

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.


Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Amidas/química , Aminoquinolinas/química , NAD/metabolismo , Quinolinas/química , Amidas/síntesis química , Amidas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Hidrólisis , Hígado/metabolismo , Membranas Artificiales , Ratones Endogámicos C57BL , Modelos Moleculares , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Permeabilidad , Conformación Proteica , Quinolinas/síntesis química , Quinolinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad
8.
Invest Ophthalmol Vis Sci ; 43(9): 3016-20, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12202524

RESUMEN

PURPOSE: Studies have shown that adenosine A(1) agonists can lower IOP in rabbits, mice, and monkeys, and this response is mediated in part by increases in outflow facility. The purpose of this project was to evaluate the response of trabecular meshwork cells to the addition of the adenosine A(1) receptor agonist N(6)-cyclohexyladenosine (CHA). METHODS: The human trabecular meshwork (HTM-3) cell line and primary cultures of bovine trabecular meshwork (BTM) cells were used in these studies. Cells were treated with CHA, and the secretion of matrix metalloproteinase (MMP)-2 or the activation of extracellular signal-regulated kinase (ERK1/2) was determined. RESULTS: Treatment of HTM-3 and BTM cells with CHA (0.1 micro M) resulted in a time-dependent secretion of MMP-2 that was measurable as early as 30 minutes after treatment and reached a maximum by 2 hours. This CHA-induced secretion of MMP-2 was inhibited by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) and by the ERK1/2 pathway inhibitor U0126. Treatment of HTM-3 cells with CHA produced a rapid dose-dependent activation of ERK1/2 with an EC(50) of 5.7 nM. The CHA-induced activation of ERK1/2 was inhibited by pretreatment with the adenosine A(1) antagonist CPT and by the ERK pathway inhibitor U0126. CONCLUSIONS: The addition of the adenosine A(1) agonist CHA stimulates the secretion of MMP-2 from trabecular meshwork cells. This secretory response involves the activation of adenosine A(1)-linked stimulation of ERK1/2. These results provide evidence for the existence of functional adenosine A(1) receptors in the trabecular cells and that the activation of these receptors stimulates secretion of MMP-2.


Asunto(s)
Adenosina/análogos & derivados , Metaloproteinasa 2 de la Matriz/metabolismo , Receptores Purinérgicos P1/metabolismo , Teofilina/análogos & derivados , Malla Trabecular/efectos de los fármacos , Adenosina/farmacología , Animales , Bovinos , Línea Celular Transformada , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos , Humanos , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Teofilina/farmacología , Factores de Tiempo , Malla Trabecular/metabolismo
9.
Artículo en Inglés | MEDLINE | ID: mdl-23797207

RESUMEN

BACKGROUND: We recently validated in cross-sectional studies a new method to determine total body creatine pool size and skeletal muscle mass based on D3-creatine dilution from an oral dose and detection of urinary creatinine enrichment by isotope ratio mass spectrometry (IRMS). Routine clinical use of the method in aging and disease will require repeated application of the method, with a more widely available technology than IRMS, to enable determination of change in skeletal muscle mass in longitudinal studies. We therefore adapted the method to liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, and sought to establish proof of concept for the repeated application of the method in a longitudinal study. Because the turnover of creatine is slow, it was also critical to determine the impact of background enrichment from an initial dose of oral D3-creatine on subsequent, longitudinal measurements of change in muscle mass. METHODS: Rats were given an oral tracer dose of D3-creatine (1.0 mg/kg body weight) at 10 and 17 weeks of age. LC-MS/MS was used to determine urinary D3-creatine, and urinary D3-creatinine enrichment, at time intervals after D3-creatine administration. Total body creatine pool size was calculated from urinary D3-creatinine enrichment at isotopic steady state 72 h after administration of D3-creatine tracer. RESULTS: At 10 weeks of age, rat lean body mass (LBM) measured by quantitative magnetic resonance correlated with creatine pool size (r = 0.92, P = 0.0002). Over the next 7 weeks, the decline in urinary D3-creatinine enrichment was slow and linear, with a rate constant of 2.73 ± 0.06 %/day. Subtracting background urinary D3-creatinine enrichment from the elevated enrichment following a second dose of D3-creatine at 17 weeks permitted repeat calculations of creatine pool size. As at 10 weeks, 17-week LBM correlated with creatine pool size (r = 0.98, P <0.0001). In addition, the change in creatine pool size was correlated with the change in LBM during the 7 weeks of rat growth between measurements (r = 0.96, P <0.0001). CONCLUSION: The LC-MS/MS-based D3-creatine dilution method can be applied repeatedly to measure total body creatine skeletal muscle mass change in longitudinal study.

10.
J Appl Physiol (1985) ; 112(11): 1940-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22422801

RESUMEN

There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3)-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.


Asunto(s)
Creatina/farmacocinética , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Animales , Creatina/sangre , Creatina/orina , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Metilación , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
11.
J Med Chem ; 55(16): 7061-79, 2012 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-22891645

RESUMEN

The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC(50) = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1ß/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.


Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Cartílago Articular/efectos de los fármacos , Bases de Datos de Compuestos Químicos , Osteoartritis/patología , Sulfonamidas/síntesis química , Triazinas/síntesis química , Proteína ADAMTS5 , Agrecanos/metabolismo , Animales , Cartílago Articular/metabolismo , Cartílago Articular/patología , Endopeptidasas/metabolismo , Epítopos , Glicosaminoglicanos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Osteoartritis/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Triazinas/farmacocinética , Triazinas/farmacología
12.
J Med Chem ; 53(4): 1857-61, 2010 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-20128594

RESUMEN

4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.


Asunto(s)
Benzamidas/síntesis química , PPAR delta/antagonistas & inhibidores , Sulfonas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzamidas/farmacocinética , Benzamidas/farmacología , Sitios de Unión , Carnitina O-Palmitoiltransferasa/biosíntesis , Carnitina O-Palmitoiltransferasa/genética , Línea Celular Tumoral , Cisteína/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Genes Reporteros , Humanos , Ligandos , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/enzimología , PPAR delta/agonistas , PPAR delta/genética , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Relación Estructura-Actividad , Sulfonas/farmacocinética , Sulfonas/farmacología , Distribución Tisular , Transcripción Genética/efectos de los fármacos
13.
J Med Chem ; 52(24): 7962-5, 2009 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-19902954

RESUMEN

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.


Asunto(s)
Isoxazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Perros , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/administración & dosificación , Humanos , Isoxazoles/química , Isoxazoles/farmacocinética , Ratas
14.
Antimicrob Agents Chemother ; 51(8): 2898-904, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17562804

RESUMEN

Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.


Asunto(s)
Antimaláricos , Pirroles , Quinazolinas , Administración Oral , Animales , Anorexia/inducido químicamente , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Disponibilidad Biológica , Hidrólisis , Masculino , Dosis Máxima Tolerada , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/metabolismo , Pirroles/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Ratas , Ratas Sprague-Dawley
15.
Exp Eye Res ; 76(3): 283-9, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12573657

RESUMEN

Kinins and prostaglandins activate signalling pathways in cells of the trabecular meshwork and have opposing effects on outflow resistance to aqueous humor. Consequently, interactions between these pathways may be important in the regulation of intraocular pressure. In the present study, the influence of bradykinin on PGE(2) signalling was examined in primary cultures of bovine trabecular meshwork cells. Incubation of cells with bradykinin produced a concentration-dependent (EC(50)=3.6+/-0.7 nM) elevation of intracellular free Ca(2+). At a maximal concentration of 100 nM, the increase in Ca(2+) was rapid, peaking in 30 sec, and then slowly returned to baseline. This effect was completely inhibited in cells pretreated with the selective B(2) kinin receptor antagonist, Hoe-140. Treatment of trabecular meshwork cells with PGE(2), in comparison, had no effect on cellular Ca(2+) but produced a concentration-dependent increase in adenosine 3', 5'-cyclic monophosphate (cAMP) formation. Bradykinin had no effect on basal cAMP. However, incubation of cells with PGE(2) in combination with bradykinin resulted in a 3- to 5-fold enhancement of PGE(2)-stimulated cAMP production. Bradykinin enhancement of cAMP stimulation was concentration-dependent with an EC(50) of 3.6+/-1.8 nM. Treatment of cells with bradykinin increased the response maximum for PGE(2) signalling, while the EC(50) for PGE(2) was not changed. This action of bradykinin was again blocked in cells pretreated with Hoe-140. Bradykinin also produced a 2- to 3-fold increase in isoproterenol and cholera toxin-stimulated cAMP accumulation. However, when adenylyl cyclase was stimulated directly with forskolin, bradykinin failed to alter cAMP production. These results indicate that bradykinin activates B(2) kinin receptors in trabecular meshwork cells to amplify PGE(2)-stimulated cAMP formation by facilitating the interaction between activated G(s) and the catalytic unit of adenylyl cyclase.


Asunto(s)
Bradiquinina/farmacología , Dinoprostona/farmacología , Malla Trabecular/efectos de los fármacos , Animales , Calcio/metabolismo , Bovinos , Células Cultivadas , AMP Cíclico/biosíntesis , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Endotelina-1/farmacología , Transducción de Señal/efectos de los fármacos , Malla Trabecular/citología , Malla Trabecular/metabolismo
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