| Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications -> Monitor Keywords |
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Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complicationsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Plural Six-membered Hetero Rings Consisting Of One Nitrogen And Five Carbon AtomsNovel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070249682, Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to novel CD40:CD154 binding interrupter compounds and use of these compounds and pharmaceutical compositions comprising them, to treat conditions associated with inappropriate CD154 activation in a subject. Specifically, this invention provides compounds which are identified by screening a library of small molecules for those that are capable of specifically binding CD154 and interrupting CD40:CD154 interaction. BACKGROUND OF THE INVENTION [0002] Data establishing that T cell activation requires both T cell receptor ("TCR") mediated signals and simultaneously delivered costimulatory signals have accumulated over the past twenty years. For example, antibody production by B lymphocytes in response to protein antigens requires a specific, costimulatory interaction with T lymphocytes. This B cell/T cell interaction is mediated through several receptor-ligand binding events in addition to engagement of the TCR. See, e.g., Noelle et al. Immunology Today 13: 431-433 (1992). See also Hollenbaugh et al. EMBO J. 11: 4313-4321 (1992). These additional binding events include the binding of CD40 on B cells to CD154 (CD40L, and also known as gp39, T-BAM, 5c8 antigen, CD40CR and TRAP) on T cells. Human CD40 is a 50 kilodalton cell surface protein expressed on mature B cells, as well as macrophages, dendritic cells, fibroblasts and activated endothelial cells. CD40 belongs to a class of receptors involved in cell signalling and in programmed cell death, including Fas/CD95 and the tumor necrosis factor (TNF) alpha receptor. Human CD154, a 32 kD type II membrane glycoprotein having homology to TNF alpha, is a member of the TNF family of receptors and is transiently expressed primarily on activated T cells. CD40:CD154 binding has been shown to be required for T cell-dependent antibody responses. In particular, CD40:CD154 binding provides anti-apoptotic and/or lymphokine stimulatory signals. See, e.g., Karpusas et al. Structure 15, 1021-1039 (1995), U.S. patent application Ser. No. 09/180,209 and WO97/00895, the disclosures of all of which are hereby incorporated by reference. [0003] The importance of CD40:CD154 binding in promoting T cell dependent biological responses is underscored by the development of X-linked hyper-IgM syndrome (X-HIGM) in humans lacking functional CD154. These individuals have normal or high IgM levels, but fail to produce IgG, IgA or IgE antibodies. Affected individuals suffer from recurrent, sometimes severe, bacterial infection (most commonly Streptococcus pneumoniae, Pneumocystis carinii and Hemophilus influenzae) and certain unusual parasitic infections, as well as an increased incidence of lymphomas and abdominal cancers. These clinical manifestations of disease can be managed through intravenous immunoglobulin replacement therapy. [0004] The effects of X-HIGM are simulated in animals rendered nullizygous for the gene encoding CD154 (knockout animals). Studies with nullizygotes have confirmed that, while B cells can produce IgM in the absence of CD40:CD154 binding, they are unable to undergo isotype switching, or to survive normally and undergo affinity maturation. In the absence of a functional CD40:CD154 interaction, spleen and lymph node germinal centers do not develop properly, and the development of memory B cells is impaired. These defects contribute to a severe reduction or absence of a secondary (mature) antibody response. [0005] Individuals with X-HIGM and CD154 nullizygotes also have defects in cellular immunity. These defects are manifested by an increased incidence of Pneumocystis carinii, Histoplasma capsulatum, Cryotococcus neoformans infection, as well as chronic Giardia lambli infection. Murine nullizygotes are deficient in their ability to fight Leishmania infection. Many of these cell-mediated defects are reversible by administration of IL-12 or IFN-gamma. These data substantiate the view that CD40:CD154 binding promotes the development of Type I T-helper cell responses. Further support is derived from the observation that macrophage activation is defective in CD154-deficient settings, and that administration of anti-CD154 antibodies to mice diminished their ability to clear Pneumocystis infection. Blockade of CD40:CD154 binding appears to reduce the ability of macrophages to produce nitric oxide, which mediates many of the macrophages' pro-inflammatory activities. It should be noted, however, that mammals (including humans) who lack functional CD154 do not develop significant incidences of viral infection. [0006] A number of preclinical studies, including those described in co-pending, commonly assigned PCT patent applications published as WO98/30241, WO98/30240, WO98/52606, WO98/58669 and WO99/45958, describe the promise of agents capable of interrupting CD40:CD154 binding as immunomodulating agents. In murine systems, antibodies to CD154 block primary and secondary immune responses to exogenous antigens, both in vitro and in vivo. Antibodies to CD154 cause a reduction in germinal centers in mice and monkeys, consistent with data on CD154 immunodeficiency. Administration of three doses of anti-CD154 antibody to lupus-prone mice, age three months, substantially reduced titers against double-stranded DNA and nucleosomes, delayed the development of severe nephritis, and reduced mortality. Moreover, administration of anti-CD154 antibodies to mice age five to seven months with severe nephritis was shown to stabilize or even reverse renal disease. Anti-CD154 antibodies given concomitantly with small resting allogeneic lymphocytes permitted unlimited survival of mouse pancreatic islet allografts. In other animal models, interference with CD40:CD154 binding has been demonstrated to reduce symptoms of autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease), graft rejection (e.g., cardiac allograft, graft-versus-host disease), and mercuric chloride induced glomerulonephritis, which is mediated by both humoral and cellular mechanisms. [0007] Such studies with anti-CD154 antibodies demonstrate the role of CD154 as a critical target for modulating immune responses. [0008] These studies establish the utility of CD40:CD154 binding interrupters as therapeutic agents. As a result, they also suggest the potential of novel CD40:CD154 binding interrupters. SUMMARY OF THE INVENTION [0009] The present invention provides novel compounds, other than anti-CD154 antibodies and soluble CD40 or CD40 fusion proteins, that specifically bind CD154 and interrupt CD40:CD154 interaction. This invention also provides pharmaceutical compositions comprising these compounds. The invention also provides methods using these compounds to treat conditions associated with inappropriate CD154 activation. [0010] The foregoing and other objects, features and advantages of the present invention, as well as the invention itself, will be more fully understood from the following description of preferred embodiments. DETAILED DESCRIPTION OF THE INVENTION [0011] The following discussion illustrates and exemplifies the variety of contexts and circumstances in which the invention can be practiced, as well as providing specific embodiments of the invention. Novel CD40:CD154 Binding Interruptors [0012] In a preferred embodiment, this invention provides a generic compound, which binds to CD154 and preferably interrupts CD40:CD154 interaction, represented by the formula (Formula I): wherein: [0013] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of H, C1-5 alkyl, C1-5 alkyl-aryl, C1-5 alkyl-cycloalkyl, C1-5 alkyl-heteroaryl, C1-5 alkenyl-heterocyclo, cycloalkyl, cycloalkyl-aryl, C1-5 alkenyl-aryl, CR.sup.gR.sup.hCO.sub.2H and CR.sup.gR.sup.hCO.sub.2alkyl; wherein aryl or heteroaryl are optionally substituted with one to four substituents selected from R.sup.d and alkyl is optionally substituted with R.sup.i; or R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6, and R.sup.7 and R.sup.8 independently form, together with the nitrogen to which they are attached, a 5-6 membered ring which is optionally substituted with a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, wherein the nitrogen may optionally be substituted with alkyl or alkyl-aryl and the ring may optionally be substituted with R.sup.j; [0014] R.sup.a, R.sup.b and R.sup.c are independently selected from the group consisting of H, alkyl and alkyl-aryl; [0015] R.sup.d is selected from the group consisting of halogen, alkyloxy, NO.sub.2, NH.sub.2, alkyl, SO.sub.2NH.sub.2, hydroxyl and aryl; [0016] R.sup.e and R.sup.f are independently selected from the group consisting of H, alkyl and cycloalkyl; or R.sup.eR.sup.f together with the atom to which they are attached form a 4-7 membered ring containing zero to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein R.sup.eR.sup.f together with the atom to which they are attached may be fused to one or two aromatic rings; [0017] R.sup.g and R.sup.h are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, alkyl-aryl and alkyl-cycloalkyl; wherein alkyl is optionally substituted with R.sup.k; and aryl is optionally substituted with R.sup.l; or R.sup.gR.sup.h together with the carbon to which they are attached form a 5-8 membered ring which may be bicyclic; [0018] R.sup.i is selected from the group consisting of: NR.sup.eR.sup.f, alkyloxy, aryloxy, C(O)aryl, aryl, OC(O)alkyl, alkylaryloxy and hydroxyl; wherein alkyl is optionally substituted with halogen and aryl is optionally substituted with R.sup.d; [0019] R.sup.j is selected from the group consisting of (CH.sub.2).sub.yNR.sup.eR.sup.f, (CH.sub.2).sub.zOH, CO.sub.2H, C(O)N(alkyl).sub.2, C(O)NH.sub.2, alkylaryl and aryl; [0020] wherein aryl is optionally substituted with one to four substituents selected from R.sup.d; [0021] R.sup.k is selected from the group consisting of C(O)NH.sub.2, C(O)OH, alkylthio, NH.sub.2, heteroaryl, heteroalkyl, NHC(NH)NH.sub.2, C1-5 alkylhydroxyl, hydroxyl and alkyloxy; [0022] R.sup.1 is selected from the group consisting of hydroxyl, NO.sub.2 and C1-5 alkyl; [0023] U is selected from the group consisting of O, S(O).sub.y, NR.sup.c, NR.sup.cC(O), NR.sup.cCO(O)NR.sup.c; [0024] W is selected from the group consisting of (CR.sup.aR.sup.b), (CR.sup.aR.sup.b).sub.yU(CR.sup.aR.sup.b).sub.y, C2-3 alkynyl, C2-3 alkenyl; [0025] each X is independently 0-3; [0026] each Y is independently 0-2; [0027] each Z is independently 1-2. [0028] "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. [0029] "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. [0030] "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentenyl, 2-heptynyl and the like. "Cycloalkyl" means mono- or bicyclic saturated carbocyclic rings, each of which have from 3 to 10 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. [0031] "Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. The term also includes an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of an aryl group include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3 dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like. [0032] "Heteroaryl" means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like. [0033] "Heterocyclyl" means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "heterocyclyl" include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4 pyridones attached through the nitrogen or N-substituted-(1H,3H) pyrimidine-2,4-diones (N-substituted uracils). [0034] "Halogen" includes fluorine, chlorine, bromine and iodine. Continue reading about Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications... Full patent description for Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Novel cd40:cd154 binding interruptor compounds and use thereof to treat immunological complications patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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