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1.
Arch Pharm Res ; 38(6): 1019-32, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25599616

ABSTRACT

Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that ß-arrestin signaling mediates niacin-induced flushing, but not its anti-lipolytic effect, we tried to find GPR109A agonists which selectively elicit Gi-protein-biased signaling devoid of ß-arrestin internalization using a ß-lactamase assay. We identified a 4-(phenyl)thio-1H-pyrazole as a novel scaffold for GPR109A agonist in a high throughput screen, which has no carboxylic acid moiety known to be important for binding. While 1-nicotinoyl derivatives (5a-g, 6a-e) induced ß-arrestin recruitment, 1-(pyrazin-2-oyl) derivatives were found to play as G-protein-biased agonists without GPR109A receptor internalization. The activity of compound 5a (EC50 = 45 nM) was similar to niacin (EC50 = 52 nM) and MK-6892 (EC50 = 74 nM) on calcium mobilization assay, but its activity at 10 µM on ß-arrestin recruitment were around two and five times weaker than niacin and MK-6892, respectively. The development of G-protein biased GPR109A ligands over ß-arrestin pathway is attainable and might be important in differentiation of pharmacological efficacy.


Subject(s)
Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Arrestins/drug effects , CHO Cells , Calcium Signaling/drug effects , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/pharmacology , High-Throughput Screening Assays , Humans , Indicators and Reagents , Niacin/pharmacology , Oxadiazoles/pharmacology , Receptors, Nicotinic , Structure-Activity Relationship , beta-Arrestins , beta-Lactamases/chemistry
2.
Bioorg Med Chem Lett ; 23(6): 1763-7, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23411081

ABSTRACT

Saturated fatty acids (FA) were grafted using tyrosine as a spacer group to the cyclotriphosphazene ring along with equimolar hydrophilic methoxy poly(ethylene glycol) (MPEG) in cis-nongeminal way. Seven new cyclotriphosphazene amphiphiles were prepared from combinations of hydrophilic MPEGs with different molecular weights of 350, 550, 750 and 1000 and four different fatty acids of different hydrophobicity including lauric, myristic, palmitic and stearic acids. These steric amphiphiles bearing fatty acids as a hydrophobic group were found to form more stable micelles with very low critical micelle concentrations (CMC) (2.95-7.80mg/L) compared with oligopeptide analogues, and their highly hydrophobic core environment is unique and potentially useful for various biomedical applications.


Subject(s)
Fatty Acids/chemistry , Drug Carriers/chemical synthesis , Drug Carriers/chemistry , Hydrophobic and Hydrophilic Interactions , Micelles , Molecular Weight , Nitriles/chemistry , Particle Size , Polyethylene Glycols/chemistry
3.
Int J Pharm ; 422(1-2): 374-80, 2012 Jan 17.
Article in English | MEDLINE | ID: mdl-22079718

ABSTRACT

Docetaxel micelle-encapsulated by a tripodal cyclotriphosphazene amphiphilile [NP(PEG750)(GlyPheLeu)(2)Et](3) (CP750) exhibited outstanding drug-loaded micelle stability in aqueous solution compared with the polymeric micelles assembled from linear block copolymers. Furthermore, docetaxel micelle-encapsulated by CP750 is obtainable in solvent free powder form, which is immediately soluble in any aqueous media including saline and PBS and very stable to photo-degradation even in the room light at room temperature. Although docetaxel micelle-encapsulated by CP750 did not display highly improved pharmacokinetic profile compared with Taxotere currently in clinical use, its in vivo xenograft trials exhibited excellent antitumor efficacy by showing complete tumor regression against the breast cancer cells (MDA-MB-231) at a lower dose of 5mg/kg and better efficacy against gastric cancer cells (MKN-28) compared with Taxotere. Furthermore, according to the comparative acute toxicity study, toxicities associated with Taxotere may be remarkably reduced by micelle-encapsulation of docetaxel using CP750, which afforded a much higher LD(50) value of 75 mg/kg compared with 28 mg/kg of docetaxel in Taxotere. Thus docetaxel micelle-encapsulated by CP750 has entered the stage of preclinical studies.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Carriers , Peptides/chemistry , Polyethylene Glycols/chemistry , Taxoids/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Breast Neoplasms/pathology , Cell Line, Tumor , Chemistry, Pharmaceutical , Docetaxel , Drug Compounding , Drug Stability , Female , Humans , Injections, Intravenous , Lethal Dose 50 , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Micelles , Photolysis , Rats , Rats, Sprague-Dawley , Stomach Neoplasms/pathology , Taxoids/administration & dosage , Taxoids/chemistry , Taxoids/pharmacokinetics , Taxoids/toxicity , Technology, Pharmaceutical/methods , Tumor Burden , Xenograft Model Antitumor Assays
4.
J Control Release ; 147(1): 144-50, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20654662

ABSTRACT

A hydrophobic and water-insoluble platinum(II) compound, cis-(cha)(2)Pt(NO(3))(2) was encapsulated by macromolecular micelles self-assembled from an amphiphilic cyclotriphosphazene [NP(MPEG750)(GlyPheLeu)(2)Et](3) (CP750). The micelle-encapsulated platinum(II) compound exhibited outstanding pharmacokinetics in rats by showing long blood circulation and much larger systemic exposure (AUC=43.5 µgh/ml) compared with the free carboplatin (AUC=4.32 µgh/ml). Biodistribution study of the micellar platinum(II) compound using male Sprague-Dawley rats has shown excellent tumor to tissue ratios of 4.03 at 2h post injection and 4.67 at 24h post injection. Furthermore, the micellar platinum(II) compound exhibited more than 6 times higher cellular uptake in human cervical (HeLa) and lung (A549) tumor cells compared with the free platinum compound. Also it is surprising that the micellar platinum(II) compound displayed specifically high cytotoxicity against the stomach tumor cells (SNU638), which are one of the least responsive to chemotherapeutic agents currently in clinical use. The acute toxicity study has shown that the LD(50) values of free and the micellar cis-(cha)(2)Pt(NO(3))(2) are approximately 70 mg/kg and 90 mg/kg, respectively. Thus the platinum compound encapsulated by cyclotriphosphazene micelles is a promising candidate for preclinical studies.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Carriers/chemistry , Organoplatinum Compounds/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Humans , Hydrophobic and Hydrophilic Interactions , Lethal Dose 50 , Male , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Micelles , Organoplatinum Compounds/pharmacokinetics , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/toxicity , Rats , Rats, Sprague-Dawley , Tissue Distribution
5.
Eur J Med Chem ; 45(9): 3575-80, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20542605

ABSTRACT

Novel molecular matrices have been derived from coumarin-4-acetic acids and beta-phenylethylamines using the Bischler-Napieralski protocol which has led to the synthesis of analogues of tetrahydropapaverine in which the dimethoxybenzene moiety has been replaced by substituted coumarins. One carbon homologation has led to cyclization at the C3 position of coumarin generating the protoberberine skeleton. Structures have been confirmed by diffraction studies. The results showed that compounds 6e, 6f, 7e and 7f were found to be very effective against DNA samples of Gram positive bacterium Staphylococcus aureus and fungus Aspergillus niger.


Subject(s)
Berberine Alkaloids/chemical synthesis , Berberine Alkaloids/pharmacology , Coumarins/chemistry , DNA, Bacterial/metabolism , DNA, Fungal/metabolism , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Aspergillus niger , Berberine Alkaloids/chemistry , Berberine Alkaloids/metabolism , DNA, Bacterial/chemistry , DNA, Fungal/chemistry , Escherichia coli , Staphylococcus aureus , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/metabolism
6.
J Control Release ; 142(1): 132-7, 2010 Feb 25.
Article in English | MEDLINE | ID: mdl-19822179

ABSTRACT

Cyclotriphosphazenes grafted with equimolar amounts of a hydrophilic polyethylene glycol and a hydrophobic oligopeptide in cis-nongeminal way form a new class of tripodal amphiphiles allowing both intra- and intermolecular hydrophobic interactions that differ from linear block copolymer amphiphiles. It has been found in this study that the tripodal amphiphiles can be tuned for self-assembly from micelles to bilayered polymersomes by controlling the hydrophobicity of the oligopeptide grafted. For instance, the tripodal amphiphiles with an intermediate hydrophobicity (01) remain as stable micelles in aqueous solution. These biodegradable polymersomes exhibit outstanding physicochemical properties required for practical drug delivery and other biomedical applications. In particular, the cyclic phosphazene trimer platinated with a hydrophobic cis-bis(cyclohexylamine)Pt-moiety forms very stable polymersomes with excellent tumor selectivity by EPR effect and seems to be a promising candidate for preclinical studies.


Subject(s)
Micelles , Oligopeptides/chemistry , Surface-Active Agents/chemistry , Animals , Drug Delivery Systems , Hydrophobic and Hydrophilic Interactions , Male , Mice , Mice, Inbred C57BL , Oligopeptides/pharmacokinetics , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacokinetics , Surface-Active Agents/pharmacokinetics
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