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  Recognition of oligiosaccaride molecular targets by polycationic small molecule inhibitors and treatment of immunological disorders and infectious diseasesUSPTO Application #: 20070093424Title: Recognition of oligiosaccaride molecular targets by polycationic small molecule inhibitors and treatment of immunological disorders and infectious diseases Abstract: Small molecule polycationic agents are used to modulate or interrupt biological processes by binding to oligosaccharide-based biomolecules. Compounds that inhibit nitric oxide, TNFα or other immunomodulators are provided and are useful for treating immunological disease and disease of an infectious disorder. (end of abstract) Agent: Connolly Bove Lodge & Hutz LLP - Wilmington, DE, US Inventors: Mark R. Burns, Sunil A. David USPTO Applicaton #: 20070093424 - Class: 514014000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 12 To 15 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20070093424. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present disclosure relates to certain polycationic compounds. The present disclosure also relates to methods and compositions that can be used to define drug targets, setup screening assays and the design of agents to interrupt pathological biological processes involving carbohydrate targets. The present disclosure also relates to drug agents used to treat diseases or conditions, particularly immunological disorders and infectious diseases. [0002] Small molecule polycationic compounds bind and neutralize bacterial lipopolysaccharides, and along with test results suggest their suitability for the prevention or treatment of endotoxic shock states or sepsis. BACKGROUND [0003] Carbohydrates represent the bulk of organic matter on earth..sup.1 It has been noted that roughly 80% of secreted and cell-surface proteins are glycosylated..sup.2 The scientific field of glycobiology involves the investigation of the role that saccharide structure plays in biological function. Given the generally complex structural nature of glycoconjugates, this has been the last of the three major biological materials to be explored in great detail. Unlike proteins and nucleic acids, the biosynthesis of glycosylated biostructures does not involve a templated, message-driven production. A diverse set of enzymes operate on substrates to synthesize three main types of glycoconjugates: 1) N-linked glycoproteins, 2) O-linked glycoproteins and 3) glycosaminoglycans..sup.3 [0004] The role of oligosaccharides in biological recognition has been amply demonstrated in recent scientific literature. This role extends to cell adhesion, cell-to-cell communications and signal transduction, route to infection by bacteria and viruses, development and immunology..sup.4 It has been noted that almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins..sup.5 [0005] The specific biological recognition of saccharides is a tremendous chemical challenge, even for nature, due to their complex, irregular and multifunctional structures..sup.6 This challenge is made even more difficult by the ability of the poly-hydroxylated exteriors to associate well with water. It has been noted that the binding constant for proteins with monosaccarides peak at approximately 10.sup.7 M.sup.-1, a remarkable low value for biological molecular recognition..sup.7 This low molecular affinity for monomeric carbohydrates is magnified biologically through what has become known as the "glycoside cluster effect." This effect is manifested when carbohydrates are oligomerized, thereby maximizing binding efficiencies through not only an additive manner but also through entropic means..sup.8 [0006] X-ray structures of oligosaccharide-binding proteins have revealed that the polar groups of the carbohydrates are involved in multiple hydrogen bonding interactions with complementary polar donor and acceptor hydrogen bond sites on the protein. Nature has used this complementary interaction to a great extent in order to gain specificity and energy for binding. Furthermore, numerous salt bridges are observed between charged residues on the protein and complementary charged carboxylate, phosphate, sulfate or ammonium functions on the carbohydrate structure. It has been noted that the involvement of serine, tyrosine and threonine hydroxyl groups is relatively uncommon..sup.9 It has also been noted that most of the complementary non-polar interactions with carbohydrates involve aromatic residues on the protein binding partner..sup.10 Most of the hydrogen bonds involve planar, multivalent side chain groups (Asn, Asp, Glu, Gln, Arg, His). An additional insight was the recognition of the ability of 2-aminopyridine moiety to act as a heterocyclic mimetic of the asparagines/glutamine amide side chain..sup.11 [0007] Several examples of the detailed three-dimensional structure of polybasic protein ligands binding to anionic oligosaccharides exist. The binding interaction between fibroblast growth factor and heparin.sup.12 reveals that a significant number of positively charged protein residues interact with the negatively charged glycoconjugate receptor. It is important to recognize that many of the negatively charged species on the receptor are heterogeneously sulfated on alternating L-iduronic and D-glucosamino sugars..sup.13 X-ray analysis of the glycoprotein hormone follicle-stimulating hormone interacting with its receptor shows that a large buried interface (2600 .ANG..sup.2) with a high charge density (1.13 charges per nm.sup.2) defines a universal binding mode where charge complementarity defines specificity..sup.14 Theoretically, a large energy barrier must be overcome by desolvating the partners before binding can occur. [0008] The carbohydrate-modifying enzymes known as sulfotransferases represent an intriguing method used by nature to reversibly create anionic binding sites on biomolecules. Many literature examples exist of biological phenomena such as development, differentiation and especially immunology which are modulated by the presence or absence of sulfated glyco-conjugates..sup.15 Specifically, the effects of polyamines on blood coagulation and fibrinolysis in the presence of glycosaminoglycans (GAGs) has been examined because it is known that heparin (HP) interacts with polyamines, especially with spermine..sup.16 [0009] Recent scientific advances have greatly enabled the ability to delineate the role of specific carbohydrates in biological processes. Reviews of these advances have appeared..sup.17,18 An especially exciting development is the automated solid-phase synthesis of defined oligiosaccarides..sup.19 The interactions of heparin/heparan sulfate with various proteins have been reviewed..sup.20 Screening for inhibitors of oligiosaccharide-mediated biological events has been successfully applied to the microtiter plate format..sup.21,22 The use of surface plasmon resonance imaging has been applied to the study of protein-carbohydrate interactions..sup.23 The general uses of optical biosensors to drug discovery has also been reviewed..sup.24 Capillary electrophoresis is an additional tool used to define interactions between sulfated polysaccharides and proteins..sup.25 [0010] Interruption of carbohydrate-mediated disease processes. A report by Joosten et al. showed that a series of dendritic galabiose compounds containing a polyamido core (PAMAM-) had activity in inhibition of bacterial binding in the subnanomolar concentration levels..sup.26 A report by Yudovin-Farber showed that anti-prion agents could be produced using polycationic oligosaccharides..sup.27 Furthermore, the elimination of prion particles from infected individuals using polycationic agents has been shown..sup.28-31 Medicinal chemistry efforts towards inhibition of integrin-mediated events have been made..sup.32;33 Molecular recognition by these cell adhesive molecules known as integrin receptors on the cell surface is one of the most important biological processes not only in cell adhesion but also in fertilization, organ formation, cell migration, lymphocyte trafficking, immune response, and cancer metastasis..sup.34 Endotoxins, or lipopolysaccharides (LPS), the predominant structural component of the outer membrane of Gram-negative bacteria,.sup.35-37 play a pivotal role in septic shock, a syndrome of systemic toxicity which occurs frequently when the body's defense mechanisms are compromised or overwhelmed, or as a consequence of antibiotic chemotherapy of serious systemic infections (Gram-negative sepsis)..sup.38-41 Referred to as "blood poisoning" in lay terminology, Gram-negative sepsis is the thirteenth leading cause of overall mortality.sup.42 and the number one cause of deaths in the intensive care unit,.sup.43 accounting for more than 200,000 fatalities in the US annually..sup.44 Despite tremendous strides in antimicrobial chemotherapy, the incidence of sepsis has risen almost three-fold from 1979 through 2000.sup.45 and sepsis-associated mortality has essentially remained unchanged at about 45%.sup.46, both calling to attention the fact that aggressive antimicrobial therapy alone is insufficient in preventing mortality in patients with serious illnesses, and emphasizing an urgent, unmet need to develop therapeutic options specifically targeting the pathophysiology of sepsis. [0011] The presence of LPS in the systemic circulation causes a widespread activation of the innate immune response.sup.47;48 leading to the uncontrolled production of numerous inflammatory mediators, including tumor necrosis factor-.alpha. (TNF-.alpha.), interleukin-1.beta. (IL-1.beta.), and interleukin-6 (IL-6), primarily by cells of the monocyte/macrophage lineage,.sup.49;50 as well as others, such as nitric oxide produced by the endothelial cell,.sup.51;52 which, in concert, act to cause a frequently fatal systemic inflammatory response,.sup.53 termed `septic shock`. The toxic moiety of LPS is its structurally conserved glycolipid component called Lipid A,.sup.54 which is composed of a hydrophilic, bis-phosphorylated diglucosamine backbone, and a hydrophobic domain of 6 (E. coli) or 7 (Salmonella) acyl chains.sup.54 (FIG. 1). The pharmacophore necessary for the neutralization of lipid A.sup.55 by small molecules requires two protonatable positive charges separated by a distance of .about.14 .ANG., enabling ionic H-bonds between the cationic groups and the lipid A phosphates; in addition, appropriately positioned pendant hydrophobic functionalities are required to further stabilize the resultant complexes via hydrophobic interactions with the polyacyl domain of lipid A (for a recent review, see Ref..sup.56). These structural requisites were first identified in certain members of a novel class of compounds, the lipopolyamines, which were originally developed, and are currently being used as DNA transfection (lipofection) reagents. 57-60 In a detailed study of the effect of the hydrocarbon chain length in a homologous series of acylhomospermines, it was shown that C.sub.16 is the ideal lipophilic substituent, corresponding to maximal affinity, optimal aqueous solubility (and bioavailability), and neutralization potency..sup.61 SUMMARY [0012] The present disclosure relates to modulating or interrupting processes which comprises binding oligosaccharide-based biomolecules with small molecule polycationic agents. [0013] The present disclosure also relates to compounds represented by the formulae: [0014] wherein x is selected from the group consisting of --(CH.sub.2).sub.y--; 1, 2-C.sub.6H.sub.4--; 1,3-C.sub.6H.sub.4--; 1,4-C.sub.6H.sub.4--; and --CH.sub.2 OCH.sub.2--; [0015] y is an integer of 0-10; [0016] R is selected from the group consisting of --H, --CH.sub.3, --CH.sub.2C.sub.6H.sub.5, --CH.sub.2-3-indoline, --CH.sub.2-2-indoline, and --CH.sub.2-4-imidazole [0017] m is 0-4; [0018] n is 0-4; and [0019] R' is selected from the group consisting of --(CH.sub.2).sub.o--CH.sub.3; --(CH.sub.2).sub.o--CH.sub.2NH.sub.2; phenyl; 1-naphthyl and 2-naphthyl; [0020] o is an integer of 0-16; [0021] pharmaceutically acceptable salts thereof; and prodrugs thereof. Continue reading... Full patent description for Recognition of oligiosaccaride molecular targets by polycationic small molecule inhibitors and treatment of immunological disorders and infectious diseases Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Recognition of oligiosaccaride molecular targets by polycationic small molecule inhibitors and treatment of immunological disorders and infectious diseases patent application. Patent Applications in related categories: 20080108574 - Melanocortin receptor mediated modulation of neurogenesis - The present disclosure describes compositions and methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. 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