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1.
Artif Organs ; 34(2): 153-8, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19995361

ABSTRACT

Mechanical conditioning represents a potential means to enhance the biochemical and biomechanical properties of tissue-engineered cell constructs. Bioreactors that can simulate physiologic conditions can play an important role in the preparation of tissue-engineered constructs. Although various forms of bioreactor systems are currently available, these have certain limitations, particularly when these are used for the creation of vascular constructs. The aim of the present report is to describe and validate a novel pressure bioreactor system for the creation of vascular tissue. Here, we present and discuss the design concepts, criteria, as well as the development of a novel pressure bioreactor. The system is compact and easily housed in an incubator to maintain sterility of the construct. Moreover, the proposed bioreactor, in addition to mimicking in vivo pressure conditions, is flexible, allowing different types of constructs to be exposed to various physiologic pressure conditions. The core bioreactor elements can be easily sterilized and have good ergonomic assembly characteristics. This system is a fundamental tool, which may enable us to make further advances in bioreactor technology and tissue engineering. The novel system allows for the application of pressure that may facilitate the growth and development of constructs needed to produce a tissue-engineered vascular graft.


Subject(s)
Bioreactors , Blood Vessel Prosthesis , Equipment Design , Tissue Engineering/instrumentation , Biocompatible Materials , Cell Survival , Tissue Culture Techniques , Tissue Scaffolds
2.
PDA J Pharm Sci Technol ; 61(2): 75-87, 2007.
Article in English | MEDLINE | ID: mdl-17479715

ABSTRACT

Control of endotoxin contamination is an important issue in pharmaceutical and bioprocess manufacturing. Endotoxins can contaminate process intermediates used in pharmaceutical formulations, aqueous- and non-aqueous-based CIP fluids used in equipment and vial cleaning, and process fluids such as buffers used for chromatographic elution, diafiltration, and suspension of therapeutic protein-based drugs. A study was undertaken to evaluate the effectiveness of adsorptive-based depth and membrane filtration media in removing suspended endotoxin. The following variables were examined in order to determine their effects on endotoxin reduction: absorptive media type, residence time (flux), challenge solution pH, and interferences in endotoxin reduction as the result of challenge solution composition-water for injection, process buffer, and the presence of protein. The endotoxin removal capacities of the various media studied were also determined. The results of the study demonstrated differences in the effect on endotoxin removal of the variables evaluated. In addition, the results provide a strategy for conducting studies to select and validate an appropriate adsorptive filter media for control of endotoxin contamination.


Subject(s)
Disinfection/methods , Drug Contamination/prevention & control , Endotoxins/isolation & purification , Filtration/methods , Adsorption , Hydrogen-Ion Concentration , Membranes, Artificial , Pharmaceutical Preparations/chemistry , Reproducibility of Results , Solutions , Technology, Pharmaceutical , Time Factors
3.
Bioorg Med Chem Lett ; 16(14): 3843-6, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16697186

ABSTRACT

Homologation and cyclization back to the chiral methine of compound 3 yields achiral 4,4-disubstituted piperidine privileged structures (e.g., 8a) useful in the construction of melanocortin 4 receptor (MC4R) ligands. The piperidine nitrogen was replaced with carbon, oxygen, sulfur, and sulfone with minor erosion of binding. The methyl cyclohexane substituent was the most potent while significant affinity was still seen for smaller lipophilic groups such as ethyl.


Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptor, Melanocortin, Type 4/metabolism , Binding Sites , Carbon/chemistry , Cyclohexanes/chemistry , Ligands , Oxygen/chemistry , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Structure-Activity Relationship , Sulfones/chemistry , Sulfur/chemistry
4.
Bioorg Med Chem Lett ; 16(13): 3449-53, 2006 Jul 01.
Article in English | MEDLINE | ID: mdl-16650763

ABSTRACT

Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.


Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/drug effects , Ligands , Molecular Structure , Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Stereoisomerism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 16(9): 2341-6, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16297618

ABSTRACT

A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.


Subject(s)
Dipeptides/chemical synthesis , Dipeptides/pharmacology , Receptor, Melanocortin, Type 4/drug effects , Dipeptides/chemistry , Ligands , Molecular Structure , Piperazines/chemistry , Protein Binding , Receptor, Melanocortin, Type 4/chemistry , Stereoisomerism , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 15(20): 4611-4, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16105738

ABSTRACT

Extensive structure-activity relationship studies utilizing a beta-MSH-derived cyclic nonapeptide, Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (3), led to identification of a series of novel MC-4R selective disulfide-constrained hexapeptide analogs including Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (12). The structural modifications associated with profound influence on MC-4R potency and selectivity were ring size, ring conformation, and the aromatic substitution of the D-Phe7. These cyclic peptide analogs provide novel and enhanced reagents for use in the elucidation of melanocortin-4 receptor-related physiology, and may additionally find application in the treatment of obesity and related metabolic disorders.


Subject(s)
Disulfides/chemistry , Receptor, Melanocortin, Type 4/agonists , Chromatography, High Pressure Liquid , Mass Spectrometry , Receptor, Melanocortin, Type 4/chemistry , Structure-Activity Relationship
7.
J Med Chem ; 48(9): 3095-8, 2005 May 05.
Article in English | MEDLINE | ID: mdl-15857110

ABSTRACT

A series of novel, disulfide-constrained human beta-melanocyte stimulating hormone (beta-MSH)-derived peptides were optimized for in vitro melanocortin-4 receptor (MC-4R) binding affinity, agonist efficacy, and selectivity. The most promising of these, analogue 18, was further studied in vivo using chronic rat food intake and body weight models.


Subject(s)
Anti-Obesity Agents/chemical synthesis , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/agonists , beta-MSH/chemistry , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Cell Line , Eating/drug effects , Humans , Oligopeptides/chemistry , Oligopeptides/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship
8.
J Med Chem ; 47(3): 744-55, 2004 Jan 29.
Article in English | MEDLINE | ID: mdl-14736255

ABSTRACT

The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.


Subject(s)
Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/agonists , Animals , Binding, Competitive , Biological Availability , Cell Line , Cyclic AMP/biosynthesis , Humans , Ligands , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship
9.
Enantiomer ; 7(2-3): 139-48, 2002.
Article in English | MEDLINE | ID: mdl-12108632

ABSTRACT

This work investigates the origins of enantioselectivity of polymers imprinted with the HIV protease inhibitor, Indinavir. For the preparation of imprints of the drug, the critical interactions between the functional monomer, methacrylic acid, and Indinavir were characterized by infrared (IR) spectroscopy to explore the optimum functional monomer concentration for the polymerization. It was shown that a polymer with high selectivity and minimum non-selective binding for Indinavir was obtained when prepared with enough functional monomer to hydrogen bond with all of the functional groups of the drug without using an excess of monomer. This observation is explained in terms of a balance that is achieved in the monomer-template equilibrium during the polymerization that yields a polymer with highly selective sites and minimal non-selective sites. This paper further demonstrates that IR spectroscopy can be a valuable tool in the design and syntheses of molecular imprinted polymers.


Subject(s)
HIV Protease Inhibitors/chemistry , Indinavir/chemistry , Methacrylates/chemistry , Polymers/chemistry , Chromatography, High Pressure Liquid , Molecular Structure , Spectrophotometry, Infrared
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