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Results: 11 to 20 of 38

Publication Record


Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071.
Lebois EP, Digby GJ, Sheffler DJ, Melancon BJ, Tarr JC, Cho HP, Miller NR, Morrison R, Bridges TM, Xiang Z, Daniels JS, Wood MR, Conn PJ, Lindsley CW
(2011) Bioorg Med Chem Lett 21: 6451-5
MeSH Terms: Administration, Oral, Animals, Biological Availability, Cell Line, Central Nervous System, Humans, Muscarinic Agonists, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
Herein we report the discovery and SAR of a novel series of M(1) agonists based on the MLPCN probe, ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M(1) agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity.
Copyright © 2011 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.
Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND
(2011) J Med Chem 54: 342-53
MeSH Terms: Administration, Oral, Allosteric Regulation, Animals, Benzothiazoles, Biological Availability, Brain, Chlorobenzoates, Cocaine, Cocaine-Related Disorders, Drug Design, HEK293 Cells, Humans, Rats, Receptors, Metabotropic Glutamate, Self Administration, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added February 19, 2015
The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.
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1 Members
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17 MeSH Terms
Isothiocyanate exposure, glutathione S-transferase polymorphisms, and colorectal cancer risk.
Yang G, Gao YT, Shu XO, Cai Q, Li GL, Li HL, Ji BT, Rothman N, Dyba M, Xiang YB, Chung FL, Chow WH, Zheng W
(2010) Am J Clin Nutr 91: 704-11
MeSH Terms: Aged, Biological Availability, Brassicaceae, Case-Control Studies, China, Colorectal Neoplasms, Diet, Female, Glutathione Transferase, Humans, Isothiocyanates, Middle Aged, Odds Ratio, Polymorphism, Genetic, Risk Factors, Vegetables
Show Abstract · Added March 5, 2014
BACKGROUND - Isothiocyanates, compounds found primarily in cruciferous vegetables, have been shown in laboratory studies to possess anticarcinogenic activity. Glutathione S-transferases (GSTs) are involved in the metabolism and elimination of isothiocyanates; thus, genetic variations in these enzymes may affect in vivo bioavailability and the activity of isothiocyanates.
OBJECTIVE - The objective was to prospectively evaluate the association between urinary isothiocyanate concentrations and colorectal cancer risk as well as the potential modifying effect of GST genotypes on the association.
DESIGN - A nested case-control study of 322 cases and 1251 controls identified from the Shanghai Women's Health Study was conducted.
RESULTS - Urinary isothiocyanate concentrations were inversely associated with colorectal cancer risk; the inverse association was statistically significant or nearly significant in the GSTM1-null (P for trend = 0.04) and the GSTT1-null (P for trend = 0.07) genotype groups. The strongest inverse association was found among individuals with both the GSTM1-null and the GSTT1-null genotypes, with an adjusted odds ratio of 0.51 (95% CI: 0.27, 0.95), in a comparison of the highest with the lowest tertile of urinary isothiocyanates. No apparent associations between isothiocyanate concentration and colorectal cancer risk were found among individuals who carried either the GSTM1 or GSTT1 gene (P for interaction < 0.05).
CONCLUSION - This study suggests that isothiocyanate exposure may reduce the risk of colorectal cancer, and this protective effect may be modified by the GSTM1 and GSTT1 genes.
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3 Members
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16 MeSH Terms
Validation of bioluminescent imaging techniques.
Virostko J, Jansen ED
(2009) Methods Mol Biol 574: 15-23
MeSH Terms: Animals, Biological Availability, Fireflies, Luciferases, Luminescence, Pharmacokinetics, Substrate Specificity
Show Abstract · Added January 20, 2015
Bioluminescence imaging (BLI) is frequently cited for its ease of quantification. This fundamental strength of BLI has led to applications in cancer research, cell transplantation, and monitoring of infectious disease in which bioluminescence intensity is correlated with other metrics. However, bioluminescence measurements can be influenced by a number of factors, among them source location, tissue optical properties, and substrate availability and pharmacokinetics. Accounting for these many factors is crucial for accurate BLI quantification. A number of methods can be employed to ensure correct interpretation of BLI results and validate BLI techniques. This chapter summarizes the use of calibrated light-emitting standards, bioluminescence tomography, and post-mortem validation of luciferase expression for validating quantitative BLI measurements.
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1 Members
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7 MeSH Terms
Replacement of native adenovirus receptor-binding sites with a new attachment moiety diminishes hepatic tropism and enhances bioavailability in mice.
Schagen FH, Graat HC, Carette JE, Vellinga J, van Geer MA, Hoeben RC, Dermody TS, van Beusechem VW
(2008) Hum Gene Ther 19: 783-94
MeSH Terms: Adenoviruses, Human, Animals, Antigens, Viral, Binding Sites, Biological Availability, Capsid Proteins, Cell Line, Tumor, Erythrocytes, Female, Gene Targeting, Genetic Therapy, Genetic Vectors, Hepatocytes, Humans, Mice, Mice, Inbred C57BL, Rats, Transduction, Genetic, Viral Tail Proteins
Show Abstract · Added December 10, 2013
The in vivo efficacy of adenoviral vectors (AdVs) in gene delivery strategies is hampered by the broad tissue tropism of the virus and its efficient binding to human erythrocytes. To circumvent these limitations, we developed a prototype AdV lacking native binding sites. We replaced the adenoviral fiber with a chimeric molecule consisting of the fiber tail domain, the reovirus sigma1 oligomerization domain, and a polyhistidine tag as model targeting moiety. We also abolished the integrin-binding motif in the penton base protein. The chimeric attachment molecule was efficiently incorporated onto AdV capsids, allowed efficient propagation of AdV without requirement for complementing fiber and conferred highly specific tropism to the AdV. Importantly, the targeted AdV exhibited markedly reduced tropism for liver cells. In comparison with control AdV with native tropism, the targeted AdV showed 1000-fold reduced transduction of HepG2 cells and 10,000-fold reduced transduction of mouse liver cells in freshly isolated liver slices. After intravenous inoculation of C57BL/6 mice, the targeted AdV exhibited delayed clearance in comparison with the native AdV, leaving approximately 10-fold greater levels in the blood 2 hr after inoculation. For all tissues analyzed, the targeted AdV displayed significantly reduced in vivo transduction in comparison with the native vector. Furthermore, in contrast to the native AdV, the targeted AdV did not bind human erythrocytes. Together, our findings suggest that the targeted AdV design described here provides a promising platform for systemic in vivo gene delivery.
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1 Members
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19 MeSH Terms
A pharmacokinetic study on Z-(+/-)-2-(1-benzylindole-3-yl-methylene)azabicyclo[2.2.2]octane-3-ol; a novel radio-sensitization agent.
Al-Ghananeem AM, Albayati ZF, Malkawi A, Sonar VN, Freeman ML, Crooks PA
(2007) Cancer Chemother Pharmacol 60: 915-9
MeSH Terms: Administration, Oral, Animals, Area Under Curve, Biological Availability, Bridged Bicyclo Compounds, Heterocyclic, Chromatography, Liquid, Dose-Response Relationship, Drug, Half-Life, Injections, Intravenous, Male, Radiation-Sensitizing Agents, Rats, Rats, Sprague-Dawley, Spectrometry, Mass, Electrospray Ionization, Tissue Distribution
Show Abstract · Added March 5, 2014
PURPOSE - The purpose of this research was to characterize the pharmacokinetic parameters and to evaluate the absolute bioavailability of the targeted compound: Z-(+/-)-2-(1-benzylindole-3-yl-methylene)azabicyclo[2.2.2]octane-3-ol (BMABO), a novel radio-sensitization agent, after oral delivery.
METHODS - Sprague-Dawley rats received a single oral dose of 20 mg/kg and this was compared with intravenous administration of the compound (1 mg/kg). Blood samples were collected at different time points, and plasma BMABO concentrations were determined using a new sensitive and specific LC/MS analytical method, which utilized electrospray ionization.
RESULTS - The bioavailability of orally administered BMABO was determined by comparing plasma concentrations after oral gavage delivery with intravenous delivery. Following delivery of the oral dose, the average C (max) was 1,710 +/- 503 ng/ml, and the AUC-value was found to be 3,561 +/- 670 ng min kg/ml mg. Relative to the intravenous dose (100% bioavailability), the bioavailability was 6.2% after oral administration.
CONCLUSION - As the current studies demonstrate the novel radio-sensitization agent BMABO may have potential therapeutic valuable in cancer treatment. Further evaluation of the efficacy and toxicity of BMABO will determine the feasibility of the oral route for future clinical studies.
0 Communities
1 Members
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15 MeSH Terms
Intestinal drug transporter expression and the impact of grapefruit juice in humans.
Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, Jolicoeur E, Lee W, Leake BF, Tirona RG, Kim RB
(2007) Clin Pharmacol Ther 81: 362-70
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Adult, Aged, Aged, 80 and over, Beverages, Biological Availability, Blotting, Western, Carrier Proteins, Citrus paradisi, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Female, Fluorescent Antibody Technique, Food-Drug Interactions, Histamine H1 Antagonists, Humans, Immunohistochemistry, Intestinal Mucosa, Male, Middle Aged, Organic Anion Transporters, Pharmaceutical Preparations, RNA, Reverse Transcriptase Polymerase Chain Reaction, Terfenadine
Show Abstract · Added March 27, 2014
The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.
1 Communities
1 Members
2 Resources
25 MeSH Terms
The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: results of a phase 1 study.
Hande KR, Hagey A, Berlin J, Cai Y, Meek K, Kobayashi H, Lockhart AC, Medina D, Sosman J, Gordon GB, Rothenberg ML
(2006) Clin Cancer Res 12: 2834-40
MeSH Terms: Administration, Oral, Adult, Aged, Biological Availability, Cell Division, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neoplasms, Safety, Sulfonamides
Show Abstract · Added March 20, 2014
PURPOSE - Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on beta-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics.
EXPERIMENTAL DESIGN - ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined.
RESULTS - The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean T(max) of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 microg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months.
CONCLUSIONS - The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.
0 Communities
3 Members
0 Resources
13 MeSH Terms
Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo.
Wendt MD, Shen W, Kunzer A, McClellan WJ, Bruncko M, Oost TK, Ding H, Joseph MK, Zhang H, Nimmer PM, Ng SC, Shoemaker AR, Petros AM, Oleksijew A, Marsh K, Bauch J, Oltersdorf T, Belli BA, Martineau D, Fesik SW, Rosenberg SH, Elmore SW
(2006) J Med Chem 49: 1165-81
MeSH Terms: Aniline Compounds, Animals, Antineoplastic Agents, Biological Availability, Cell Line, Tumor, Drug Screening Assays, Antitumor, Drug Synergism, Fluorescence Polarization, Humans, Magnetic Resonance Spectroscopy, Mice, Mice, SCID, Paclitaxel, Piperidines, Protein Binding, Protein Structure, Tertiary, Serum, Serum Albumin, Stereoisomerism, Sulfonamides, Transplantation, Heterologous, Ultraviolet Rays, bcl-X Protein
Show Abstract · Added March 5, 2014
Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-X(L) function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-microM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X(L) and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-X(L) binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-X(L) with a K(i) of 0.8 nM. In a cellular assay 73R reversed the protection afforded by Bcl-X(L) overexpression against cytokine deprivation in FL5.12 cells with an EC(50) of 0.47 microM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.
0 Communities
1 Members
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23 MeSH Terms
Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects.
Gustin DM, Rodvold KA, Sosman JA, Diwadkar-Navsariwala V, Stacewicz-Sapuntzakis M, Viana M, Crowell JA, Murray J, Tiller P, Bowen PE
(2004) Cancer Epidemiol Biomarkers Prev 13: 850-60
MeSH Terms: Administration, Oral, Adolescent, Adult, Analysis of Variance, Antioxidants, Biological Availability, Carotenoids, Chromatography, High Pressure Liquid, Chylomicrons, Dose-Response Relationship, Drug, Drug Carriers, Drug Delivery Systems, Humans, Lycopene, Male, Maximum Tolerated Dose, Middle Aged, Probability
Show Abstract · Added March 5, 2014
This report details the findings of a single-dose Phase I pharmacokinetic and toxicity study of a food-based formulation of lycopene in healthy adult male subjects. Five dosing groups (n = 5 per group) were sequentially treated with increasing doses of lycopene ranging from 10 to 120 mg. Blood samples were collected for a total of 28 days (672 h) after administration of single doses of lycopene. The mean time (t(max)) to reach maximum total lycopene concentration (C(max)) ranged from 15.6 to 32.6 h. The C(max) for total lycopene ranged between 4.03 and 11.27 microg/dl (0.075-0.210 microm). Mean AUC(0-96) and elimination half-life for total lycopene ranged from 214 to 655 microg h/dl (3.986-12.201 micromol h/l) and 28.1 and 61.6 h, respectively. The changes observed in lycopene exposure parameters (e.g., C(max) and AUC(0-96)) were not proportional to increments in dose, with larger increases observed at the lowest end of the dosing range (10-30 mg). Chylomicron lycopene was measured during the first 12 h with the differences observed among the dosing groups not reaching statistical significance. These findings may reflect a process of absorption that is saturable at very low dosing levels or may be explained by the large interindividual variability in attained lycopene concentrations that were observed within each dosing group. Pharmacokinetic parameters for trans- and cis-lycopene isomers were calculated and are reported here. The formulation was well tolerated with minimal side effects, which were mainly of gastrointestinal nature and of very low grade.
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18 MeSH Terms