A novel class of human β
3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β
3-AR agonists. As observed, many of the β
...3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β
3 functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N–C bond of the ethanolamine. Compound
39 exhibited excellent functional β
3 agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (
44) via full AMES study supports further research into various new β
3-AR agonists containing the pyrrolidine moiety.
A novel class of human β
3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β
3-AR agonists. As observed, many of the β
3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β
3 functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N–C bond of the ethanolamine. Compound
39 exhibited excellent functional β
3 agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (
44) via full AMES study supports further research into various new β
3-AR agonists containing the pyrrolidine moiety.
A series of amide derived b sub(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for ...second generation b sub(3)-AR agonists for the treatment of overactive bladder. AB:
A series of amide derived β
3-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from
1, is used to lay the SAR foundation for ...second generation β
3-AR agonists for the treatment of overactive bladder.
Infection by
Bacillus anthracis is preventable by prophylactic vaccination with several naturally derived and recombinant vaccine preparations. Existing data suggests that protection is mediated by ...antibodies directed against the protective antigen (PA) component of the anthrax toxin complex. PA is an 83-kDa protein cleaved in vivo to yield a biologically active 63-kDa protein. In an effort to evaluate the potential of yeast as an expression system for the production of recombinant PA, and to determine if the yeast-purified rPA63 can protect from a lethal inhalational challenge, the sequence of the 63-kDa form of PA was codon-optimized and expressed in the yeast
Saccharomyces cerevisiae. Highly purified rPA63 isolated from
Saccharomyces under denaturing conditions demonstrated reduced biological activity in a macrophage-killing assay compared to non-denatured rPA83 purified from
Escherichia coli. Rabbits and non-human primates (NHP) immunized with rPA63 and later challenged with a lethal dose of
B. anthracis spores were generally protected from infection. These results indicate that epitopes present in the 63-kDa from of PA can protect rabbits and non-human primates from a lethal spore challenge, and further suggest that a fully functional rPA63 is not required in order to provide these epitopes.
The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of ...type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1 diabetes may allow for antigen-specific recruitment of regulatory cells to the islets following peptide immunization.
A resume can be considered as a tool to show a person's background,skills, knowledge, and experience and what he can offer that is unique for an organisation. This article covers in brief what ...information can be included in a resume. It also discusses in brief how electronic resumes are prepared and sent via email.
Knowledge Management: A Review Bansal, Alka
DESIDOC bulletin of information technology,
7/2000, Letnik:
20, Številka:
4
Journal Article
Knowledge Management: A Review The knowledge in an enterprise resides in various places such as :databases,knowledge bases,filling cabinets and people heads and is distributed right across the ...enterprise .Most often one part of an enterprise repeats work of another past simply because it is not possible to keep track of,and make use of,knowledge of other parts
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