Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-08-08
2000-09-19
Marschel, Ardin H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 187, 536 243, 536 2431, 536 2432, 536 245, 514 44, 585500, C07H 1900, C07H 2102, C07H 2104, A01N 4304
Patent
active
061214337
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the design, synthesis and application of oligomeric compounds containing monomeric units that each include a nitrogen atom plus a. "spanner," i.e. a group of atoms that spans between and connects adjacent nitrogen atoms. The monomeric units are connected together in linear or cyclic arrays. The monomeric units are substituted, via substitution on the nitrogen atom and/or substitution on the spanner with a tethered or untethered functional group. The oligomers are synthesized having either a random or a predefined sequences of units. Randomization can be effected independently at the functional functional group. The oligomers are synthesized having either a random or a predefined sequences of units. Randomization can be effected independently at the functional group or at the spanners. The functional group on each of the monomeric units provides for binding of the oligomeric structures to proteins, nucleic acids, lipids and other biological targets. In preferred embodiments, the compounds of the invention act as inhibitors of enzymes such as phospholipase A.sub.2 : as inhibitors of pathogens such as virus, mycobacterium, bacteria (gram negative and gram positive), protozoa and parasites; as inhibitors of ligand-receptor interactions such as PDGF (platelet derived growth factor), LTB4 (leukotriene B4), IL-6 and complement C5.sub.A ; as inhibitors of protein/protein interactions including transcription factors such as p50 (NF.sub.kappa B protein) and fos/jun; and for the inhibition of cell-based interactions including ICAM induction (using inducers such as IL1-.beta., TNF and LPS). In other preferred embodiments, the compounds of the invention are used as diagnostic reagents, including diagnostic reagents in the tests for each of the above noted systems, and as reagents in assays and as probes.
BACKGROUND OF THE INVENTION
Traditional processes of drug discovery involve the screening of complex fermentation broths and plant extracts for a desired biological activity or the chemical synthesis of many new compounds for evaluation as potential drugs. The advantage of screening mixtures from biological sources is that a large number of compounds are screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. The disadvantages are that many different samples must be screened and numerous purifications must be carried out to identify the active component, often present only in trace amounts. On the other hand, laboratory syntheses give unambiguous products, but the preparation of each new structure requires significant amounts of resources. Generally, the de novo design of active compounds based on the high resolution structures of enzymes has not been successful.
In order to maximize the advantages of each classical approach, new strategies for combinatorial unrandomization have been developed independently by several groups. Selection techniques have been used with libraries of peptides (see Geysen, H. M., Rodda, S. J., Mason, T. J., Tribbick, G. & Schoofs, P. G., J. Immun. Meth. 1987, 102, 259-274; Houghten, R. A., Pinilla, C., Blondelle, S. E., Appel, J. R., Dooley, C. T. & Cuervo, J. H., Nature, 1991, 354, 84-86; Owens, R. A., Gesellchen, P. D., Houchins, B. J. & DiMarchi, R. D., Biochem. Biophys. Res. Commun., 1991, 181, 402-408), nucleic acids (see Wyatt, J. R., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 1356-1360; Ecker, D. J., Vickers, T. A., Hanecak, R., Driver, V. & Anderson, K., Nucleic Acids Res., 1993, 21, 1853-1856) and nonpeptides (see Simon, R. J., et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 9367-9371; Zuckermann, R. N., et al., J. Amer. Chem. Soc., 1992, 114, 10646-10647; Bartlett, Santi, Simon, PCT WO91/19735; and Ohlmeyer, M. H., et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 10922-10926). The techniques involve iterative synthesis and screening of increasingly simplified subsets of oligomers. Monomers or sub-monomers that have been utilize
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Cook Phillip Dan
Kung Pei Pei
Sanghvi Yogesh S.
ISIS Pharmaceuticals Inc.
Marschel Ardin H.
Riley Jezia
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