WO2011156632A2 - Compositions et procédés de traitement de tumeurs dans le système nerveux - Google Patents

Compositions et procédés de traitement de tumeurs dans le système nerveux Download PDF

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WO2011156632A2
WO2011156632A2 PCT/US2011/039847 US2011039847W WO2011156632A2 WO 2011156632 A2 WO2011156632 A2 WO 2011156632A2 US 2011039847 W US2011039847 W US 2011039847W WO 2011156632 A2 WO2011156632 A2 WO 2011156632A2
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alkyl
alkoxy
compound according
cancer
disease
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WO2011156632A3 (fr
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Milton L. Brown
Mira O. Jung
Sivanesan Dakshanamurthy
Fraser C. Henderson
Yali Kong
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Georgetown University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention relates particularly to compounds and compositions and the use of inhibitors and modulators for p75 NTR tumor necrosis factor receptors.
  • GBM Glioblastoma multiforme
  • BBB blood brain barrier
  • Described herein are compounds, compositions and methods for preventing and treating tumors of the nervous system, by means of compounds that inhibit or modulate p75 neurotrophic receptors (p75 NTR ).
  • X can be hydrogen, lower alkyl, haloalkyl or an electron withdrawing group
  • R 1 and R 3 can either both present or both absent, and
  • R 1 and R 3 each can independently be unsubstituted lower alkyl, alkyl, halide and optionally together form a bridge
  • R 2 and R 4 can each be double bonded O
  • Z 1 and Z 2 can each be an N bearing no double bonds
  • R 1 and R 3 are absent then R 2 and R 4 can each be H or be double bonded O
  • the six- member ring can have 0-3 double bonds
  • Z 1 and Z 2 can independently be C or N
  • the six-member ring if carbocyclic can optionally be substituted;
  • R 1 , R 2 , R 3 and R 4 can independently be present or absent, and if R 1 , R 2 , R 3 and R 4 are present then each can independently be H, halide, lower alkoxy, lower alkyl, hydroxyl or haloalkyl;
  • R 5 or R 6 can be present, can be bonded to a nitrogen atom having two single bonds in the five-member ring, and the other nitrogen atom in the five-member ring can be unsubstituted or substituted and bears a double bond in the ring, if R 5 or R 6 is bonded to a nitrogen that bears a double bond then R 5 or R 6 can be alkyl or halide, and R 5 or R 6 can be of the form -linker-R 7 , wherein
  • one or more of the methylene groups can optionally be substituted independently by a respective R B , wherein each R B can be lower alkyl and its identity can be independent of the identity of R A and of respective R B on other methylene groups in the linker, and
  • R A and a respective R B can together form a bridge; and R 7 can be an end group that can be: Ci -C 8 alkyl; C3-C8 cycloalkyl; aryl, het- eroaryl, C3-C10 heterocyclic; or a 5-member heteroaryl ring having up to three heteroatoms that can be selected from O, N and S, wherein the heteroaryl ring can optionally bear a substituent R 8 ; and wherein
  • R 8 can be H, an electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, an optionally substituted fused benzo group, or
  • R 8 can be optionally a six-member heteroaryl ring in which the heteroatoms can be 1 or 2 nitrogen atoms, and R 8 can optionally be substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy;
  • R 9 can be can be of the form -linker-R 7 , wherein
  • R A can be H or independently unsubstituted Ci-Cs ,
  • one or more of the methylene groups can optionally be substituted independently by a respective R b , wherein each R b can be lower alkyl and its identity can be independent of the identity of R a and of respective R b on other methylene groups in the linker,
  • R a and a respective R b can together form a bridge
  • R 10 can be H or substituted or unsubstituted lower alkyl
  • each of R I S , R 16 , R 17 and R 18 can independently be H, an electron withdrawing group, lower alkyl, lower alkoxy, OH, or together forms a benzo substituent with a neighboring group from another of R 15 , R 16 , R 17 and R 18 , except that R 16 is not F when the remainder of the molecule has the formula C14H 16N2O2;
  • a and b can be hydrogen atoms bonded to the phenyl ring and c, respectively, but not to each other, or together a and b can form a bond; and g and h can be hydrogen atoms bonded to the phenyl ring and f, respectively, but not to each other, or together g and h can form a bond; wherein at least one of the pairs a-b and g-h is a bond;
  • R 19 and R 20 can have the form -linker-R 2S , and the other of R 19 and R 20 can be H, an electron withdrawing group, lower alkyl, lower alkoxy, OH, or can be a pi bond to the carbon atom at e, wherein:
  • R 25 is an end group that can be a lower hydrocarbon moiety.
  • the invention provides a method of preventing and treating tumors of the nervous system, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition that inhibits p75 NT and prevents the spread of tumors in healthy nervous tissue.
  • the invention provides a method of preventing and treating tumors of the nervous system, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition that inhibits p75 NTR and prevents the spread of tumors in healthy nervous tissue, wherein the composition comprises a compound or a pharmaceutically acceptable salt, solvate, clath- rate, or prodrug thereof having the formula:
  • R a can H or independently unsubstituted lower alkyl
  • one or more of the methylene groups if present can be optionally substituted independently by a respective R b , wherein each R b can be lower alkyl, heteroaryl, or optionally substituted phenyl, and the identity of each R b can be independent of the identity of R a and of respective R b on other methylene groups in the linker; and
  • R a and a respective R b can together form a bridge
  • 14. 1 can be an end group that can be: a Ci-Ci 0 hydrocarbon moiety; C3-C10 aryl, C3-C10 cycloalkyl, C3-C9 heterocyclic; optionally substituted indenyl; optionally substituted phenyl; or a 5- or 6- member heteroaryl ring having up to three heteroa- toms selected from O, N and S, wherein the heteroaryl ring can optionally bear a sub- stituent J; and wherein
  • J can bean electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, optionally substituted phenyl, or can optionally be substituted fused benzo group, or
  • J can optionally be a six-member heteroaryl ring in which the heteroatoms are 1 or 2 nitrogen atoms, and J is optionally substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy.
  • X can be hydrogen, lower alkyl, haloalkyl or an electron withdrawing group
  • R can be
  • 45125566V I R a can be H or independently unsubstituted C 1-C3;
  • n and m can independently be 1 , 2, 3 or 4
  • R 7 can be an end group that can be: Ci-C 8 alkyl; Ci-C 6 alkoxy, C3-C 8 cycloalkyl; aryl, heteroaryl, C3-C
  • R 8 can be H, an electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, an optionally substituted benzo group, substituted fused benzo group, or
  • R 8 can optionally be a six-member heteroaryl ring in which the heteroatoms is 1 or 2 nitrogen atoms, and R is optionally be substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy,
  • R 1 1 can be H, C -Ce alkyl, C
  • R 12 can be H, C
  • R l 3 can be R 8 .
  • R 8 can be H, C 1 -C3 alkyl, C 1 -C3 alkoxy, halide, hyd
  • R l 2 can be H, Q-C6 alkyl, C ⁇ -Ce alkoxy, halide or hydroxyl; and R 14 can be H, C ⁇ -Ce alkyl, Ci-C 6 alkoxy, halide or hydroxyl.
  • R 5 can be any organic radical
  • Figure 1 shows the structure based assay of inhibitors of p75 NTR NGF interactions.
  • FIG. 21 Figure 2A and 2 B shows a NGF displacement assay for p75 NTR .
  • the assay was performed using the extracellular domain of glycosylated p75 NTR .
  • 96-well plates were incubated in humidity chamber with p75 NTR Fc protein (R & D Systems) overnight at 4°C in binding buffer followed by incubation in humidity chamber with blocking buffer for 1 h at room temperature.
  • NGF and different concentrations of compounds A-G were added to wells and incubated for 6 h with shaking at room temperature. Plates were then washed with TBST and incubated in humidity chamber with antibody against NGF overnight at 4°C.
  • Figure 3 shows a competition assay for p75 NTR .
  • NGF and BDNF binding competition to p75 NTR was performed using the extracellular domain of glycosylated
  • the assay condition is similar to the protocol described above except adding NGF and BDNF together in reactions.
  • Figure 4 shows the effects of compound A on cell growth.
  • Human glioma cells were seeded in 96-well tissue culture plates. At 24 hours after seeding, a solution of the compound or DMSO vehicle control were added to each well (three replicates per concentration), and incubated for 48 hours at 37 °C. Growth inhibition was determined using CellTiter 96 ® AQ ue0 us One Solution Cell Proliferation according to manufacturer's instructions (Promega, Inc. Madison, WI), and the absorbance measured at 490 nm on a microplate reader. The 50% growth inhibition (GI50) was calculated by using the Graphpad as the compound concentration required reducing cell number by 50% compared with control.
  • GI50 50% growth inhibition
  • Figure 5 shows the results from a tube formation assay on Human Brain Microvascular Endothelial Cells (HBMEC).
  • 5A shows the control of tube formation using DMSO.
  • 5B shows the tube formation after exposure to compound A at 5 ⁇ .
  • 5C shows the total tube length of the control, compound A at 1 ⁇ , compound A at 5 ⁇ and compound A at 10 ⁇ .
  • 5D shows the total number of tubes of the control, compound A at 1 ⁇ , compound A at 5 ⁇ and compound A at 10 ⁇ .
  • Figure 6 shows the results from a tube formation assay on Human Umbilical Vein Epithelial Cells (HUVEC).
  • 6A shows the tube formation of the control.
  • 6B shows the tube formation of after exposure of compound A at 10 ⁇ .
  • 6C shows the polyhedral chambers formed.
  • 6D shows capillary networks formed.
  • Figure 7 shows the results from an in vitro rat aortical assay.
  • 7A shows the aorta of a 2 month old rat.
  • 7B shows the aorta of a 2 month old rat after exposure to 10 ⁇ of compound A for 5 days.
  • 7C shows the control of the capillary network formation.
  • 7D shows the capillary network formation of after exposure to 10 ⁇ of compound A for 5 days
  • Figure 8 shows the results from the toxicity study for compounds A-D, E, H and I.
  • GBMs expresses p75 Neurotrophic Receptor (p75 NTR ), which is only minimally expressed in low grade astrocytomas .
  • p75 NTR Neurotrophic Receptor
  • This p75 NTR is a multi-functional receptor with important roles in neurotrophin signaling, axon outgrowth, and is an important in signaling survival of oligodendroglia and neurons. It is transcriptionally regulated with spatial and temporal precision during nervous system development, injury and regeneration.
  • Egr early growth response
  • the low affinity nerve growth factor receptor p75 NTR belongs to the tumor necrosis factor receptor super-family and has been implicated in induction of apoptosis in various tissues and cell lines.
  • p75 NTR is a 75-kDa glycoprotein that binds nerve growth factor and has structural and sequential similarity to the tumor necrosis factor receptor (Chao et al., 1986, Radeke et al., 1987). This similarity indicates a role in apoptosis which was demonstrated in neuronal cells (Lee et al., 1994, Frade et al., 1996).
  • Loss of expression of p75 NTR protein is correlated with increased Gleason's score of organ confined pathological prostate tissues (Perez, M, eta al. ( 1997) Prostate 30,274-279), and is completely absent from four prostate epithelial tumor cell lines derived from metastases (Pflug, B. R. et al. ( 1 992) Cane. Res. 52, 5403-5406), indicating an inverse association of p75 NTR expression with the malignant progression of the prostate.
  • the significance of a loss of expression of p75 NTR protein during malignant transformation of prostate epithelial cells may be related to observations that this receptor appears to function in the induction of apoptosis (Barrett, G. et al.
  • p75 NTR is a divaricate "switch" trans-membrane glycoprotein in neurons, oligodendrocytes and cancer cells; the same molecule can switch on programmed cell death, or conversely promote cell survival.
  • p75 NTR has also been shown to be essential for malignant invasion of tumor cells into the CNS. Malignant stem cells are known to populate malignant Glioblastoma multiforme tumors, as well as other malignant tumors of the central nervous system (CNS). Malignant stem cells express p75 NTR , an essential component to migration of the cell into normal brain and other body tissues.
  • Methods and compounds described herein encompass the methodology to employ an agonist/ antagonist to the specific ligand (pro-NGF, NGF or BDNF) receptor, in a manner to alter the receptor molecular conformation, and thereby through consequent intra-cytoplasmic bio-molecular changes to inhibit the cell migratory transformation.
  • the methods and compounds described herein also provides the pharmacological characteristics of compounds that can bind to the p75 receptor for nerve growth factor, thereby eliminating or substantially reducing the ability of the malignant stem cell to migrate into normal tissue. While the primary goal is treatment of Glioblastoma multiforme, alternative embodiments are anticipated for other malignant tumors of the central nervous system.
  • p75 Neurotrophic Receptor is a trans-membrane glycoprotein member of the tumor necrosis factor super-family, serving as a divaricate switch to either initiate apoptosis constitutively through the intracellular "death domain", or conversely, through binding of nerve growth factor( NGF) to promote cell survival, growth and development.
  • P75 NTR binds brain derived neurotrophin factor (BDNF), neurotrophins 3,4,5, as well as proforms of NGF(proNGF). Though binding to all neurotrophins with equal affinity in most cells, p75 NTR binds to the proform of NGF with a higher affinity than the mature form.
  • BDNF brain derived neurotrophin factor
  • proNGF proforms of NGF
  • Low affinity neurotrophin receptor p75 NTR mediates glioma invasion in experimental models of glioma (in vitro and in vivo). It is expressed in both highly invasive glioma cells and in brain tumor stem cells (BTSCs). Cleavage by a gamma se- cretase is required for glioma invasion.
  • BTSCs brain tumor stem cells
  • Cleavage by a gamma se- cretase is required for glioma invasion.
  • the use of a gamma secretase inhibitor reduces invasion by established glioma lines and brain tumor stem cells that express p75 NTR .
  • Inhibitors of p75 NTR significantly inhibit glioma invasion and brain tumor stem cells that express p75 NTR .
  • the combination of a gamma secretase with an anti-angiogenic produce synergistic efficacy (by inhibiting angiogenesis and invasion) without increasing toxicities.
  • p75 NTR is a 75 kDa glycoprotein receptor that binds the neurotrophin family of growth factors, including nerve growth factor, brain- derived neurotrophic factor, neurotrophin-3 and
  • p75 NTR is necessary for malignant progression of melanoma and other tumors invading the brain (Walch, 1999) , for the migration of other neural crest cells ,such as Schwann cells (Anton, 1994), and, in the presence of NGF, for promotion of migration of melanoma cells (Shonukun, 2003). Furthermore, this effect is independent of the neurotrophic receptor tyrosine kinase (trk B) (Marchetti, 1998).
  • In vitro tumor models utilize well known cell lines of specific tumor types. Two such malignant Glioblastoma multiforme cell lines commonly used in research are U87, and U251 .
  • Johnson et al (2007) stably transfected human glioma cells (U87) with human cDNA of p75 NTR into immuno-compromised rat brains, and demonstrated that the tumors developed highly invasive edges, which expressed p75 NTR , while the controls (U87 tumor cells which contained no P75) showed no evidence of invasion and migration; the same effect was demonstrated in other more invasive glioma cell types, such as U251.
  • Forsythe's group also showed that p75 NTR mutants, which are unable to bind NGF, produce well circumscribed tumors without invasive edges, thus demonstrating that mature neurotropins are necessary for the formation of the invasive tumor phenotype. P75 NTR and NGF are thus essential for the malignant invasion of GBM cells.
  • Activation of p75 NTR with NGF or pro-NGF also causes migration of melanoma cells and increased expression of p75 NTR correlated with advanced stages and invasive potential of melanoma brain metastasis.
  • the malignant invasiveness is thought to arise from the interaction of p75 NTR interacts with the actin cytoskeleton; the small GTP-ase RhoA is a downstream effector of p75 NTR .
  • the capability of p75 NTR to modulate the activity of RhoA provides a reasonable explanation as to how p75 NTR regulation might result in changes in cellular architecture of glioma cells.
  • 6V I p75 NGF was developed to screen a virtual library of 108 million compounds for protein/protein inhibitors. Lead compounds blocking the binding site of mature NGF to p75 NTR were selected for further investigation and modification.
  • p75 Neurotrophic Receptor is a divaricate "switch" membranous glycoprotein in neurons, oligodendrocytes and cancer cells; the same molecule can switch on programmed cell death, or conversely promote cell survival. It is believed that spinal cord injury from improvised explosive devices, mortars, and similar devices can be mitigated through down-regulation of the protein. CNS tumors are the second most frequent cancer to involve young men and women. P75 NTR has also been shown to be essential for malignant invasion of tumor cells into the CNS.
  • Angiogenesis is defined as the development of a blood supply to a given area of tissue.
  • the development of a blood supply may be part of normal embryonic development, represent the revascularization of a wound bed, or involve the stimulation of vessel growth by inflammatory or malignant cells.
  • angiogenesis is defined as the proliferation of new capillaries from pre-existing blood vessels. New growth of soft tissue requires new vascularization, and the concept of angiogenesis is a key component of tissue growth and in particular, a key point of intervention in pathological tissue growth.
  • Angiogenesis is a fundamental process necessary for embryonic development, subsequent growth, and tissue repair. Angiogenesis is a prerequisite for the development and differentiation of the vascular tree, as well as for a wide variety of fundamental physiological processes including embryogenesis, somatic growth, tissue and organ repair and regeneration, cyclical growth of the corpus luteum and endometrium, and development and differentiation of the nervous system. In the female reproductive system, angiogenesis occurs in the follicle during its
  • Angiogenesis additionally occurs as part of the body's repair processes, e.g., in the healing of wounds and fractures.
  • angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating new blood vessels. Creation of the new microvascular system can initiate or exacerbate disease conditions.
  • angiogenesis is normally observed in wound healing, fetal and embryonic development, and in the formation of the corpus luteum, endometrium and placenta.
  • the process of angiogenesis has been found to be altered in a number of disease states, and in many instances, the pathological damage associated with the disease is related to uncontrolled angiogenesis. Since it was first put forward over thirty years ago, the hypothesis that angiogenesis is required for tumor growth and metastasis has gained extensive experimental support (Foikman, J. ( 1971 ) N. Engl. J. Med. 285, 1 182- 1 1 86,
  • angiogenesis is a factor in tumor growth, since a tumor must continuously stimulate growth of new capillary blood vessels in order to grow.
  • Angiogenesis is an essential part of the growth of human solid cancer, and abnormal angiogenesis is associated with other diseases such as rheumatoid arthritis, psoriasis, and diabetic retinopathy (Foikman, J. and Klagsbrun, M., Science 235:442-447,(1987)).
  • angiogenesis has also been implicated in rheumatoid arthritis, diabetic retinopathy and macular degeneration, indicating that inhibition of angiogenesis
  • Angiogenesis the formation of new blood vessels, has been implicated in the pathogenesis of several important human diseases, including cancer, diabetic retinopathy, and age-related macular degeneration. Inhibition of angiogenesis is emerging as an effective new strategy for the treatment of angiogenesis-dependent diseases.
  • GBM Glioblastoma multiforme
  • the invention employed a new paradigm that appears to be generally applicable to many types of tumors, by focusing on interrupting the cancer's mechanism for invading healthy tissue.
  • the invention developed assays to define specificity, affinity and quantification of binding of the putative tumor receptor blocking agent. And it envisioned applying the blocking agent as a drug to prevent p75 NTR -induced apoptosis after spinal cord injury, thereby significantly improving outcomes and offering hope to spinal cord injury victims.
  • the effective inhibitors discovered according to the invention were found to have structural commonalities, and to achieve their effect with surprisingly simple molecular architectures.
  • the discovered inhibitors are for the most part novel structures. Specifically, the inhibitors share a form G-H-I, in which G is a small heteroaryl or heterocyclic component such as a purine, xanthine derivative, indole, ben- zopiperidinone, or comparable structure.
  • H is a linker having typically 1 to 10 members.
  • Non-exclusive illustrative linkers comprised optionally substituted methylene backbone groups, a carbonyl backbone group, and or an amine backbone group.
  • Linkers containing an amide were particularly useful, but linkers having other configurations were also effective. In some cases the effective linkers featured an amide that formed a heterocycle between the nitrogen and another portion of the linker. It appears that the biological function of H is largely as a spacer, thus its exact composition may not be critical, though the invention is not limited to applications in which it serves only as a spacer.
  • I in the invention is a relatively small end group that that is planar or capable of adopting a largely coplanar conformation.
  • examples of I in the invention include a lower hydrocarbon moiety such as sec-butyl, as well as aryl and heteroaryl rings.
  • G-H-I is particularly effective when I comprises a heteroaryl ring such as a triazole that is further substituted by a pyridyl or pyrimidyl radical, optionally substituted.
  • the compounds of the invention resemble cellular compounds that mediate electron transfer in metabolic pathways.
  • the substituted purines of the invention are reminiscent of the cellular redox reagent NADH.
  • the benzopiperidinone structures evoke riboflavin, which is a component of the cellular redox coenzyme flavin adenine dinucleotide (FAD); the tricyclic naphthopiperidinones are even more reminiscent of riboflavin and have proved to be particularly useful.
  • the alkyl xanthines of the invention are close chemical cousins of the purines, and also have structural commonalities with the benzopiperidinones.
  • Various xanthines are antagonists of adenosine receptors, and in the brain adenosine acts to suppress neural activity. However the invention is not limited to any particular mechanism for the therapeutic effect of the invention compounds.
  • cell or like terms refer to a small usually microscopic mass of protoplasm bounded externally by a semipermeable membrane, optionally including one or more nuclei and various other organelles, capable alone or interacting with other like masses of performing all the fundamental functions of life, and forming the smallest structural unit of living matter capable of functioning independently including synthetic cell constructs, cell model systems, and like artificial cellular systems.
  • a cell can include different cell types, such as a cell associated with a specific disease, a type of cell from a specific origin, a type of cell associated with a spe-
  • a cell can also be a native cell, an engineered cell, a transformed cell, an immortalized cell, a primary cell, an embryonic stem cell, an adult stem cell, a cancer stem cell, or a stem cell derived cell.
  • Human consists of about 210 known distinct cell types.
  • the numbers of types of cells can almost unlimited, considering how the cells are prepared (e.g., engineered, transformed, immortalized, or freshly isolated from a human body) and where the cells are obtained (e.g., human bodies of different ages or different disease stages, etc).
  • Consisting essentially of in embodiments refers, for example, to a surface composition, a method of making or using a surface composition, formulation, or composition on the surface of the biosensor, and articles, devices, or apparatus of the disclosure, and can include the components or steps listed in the claim, plus other components or steps that do not materially affect the basic and novel properties of the compositions, articles, apparatus, and methods of making and use of the disclosure, such as particular reactants, particular additives or ingredients, a particular agents, a particular cell or cell line, a particular surface modifier or condition, a particular ligand candidate, or like structure, material, or process variable selected.
  • Items that may materially affect the basic properties of the components or steps of the disclosure or may impart undesirable characteristics to the present disclosure include, for example, decreased affinity of the cell for the biosensor surface, aberrant affinity of a stimulus for a cell surface receptor or for an intracellular receptor, anomalous or contrary cell activity in response to a ligand candidate or like stimulus, and like characteristics.
  • Contacting or like terms means bringing into proximity such that a molecular interaction can take place, if a molecular interaction is possible between at least two things, such as molecules, cells, markers, at least a compound or composition, or at least two compositions, or any of these with an article(s) or with a machine.
  • contacting refers to bringing at least two compositions, molecules, articles, or things into contact, i.e. such that they are in proximity to mix or touch.
  • having a solution of composition A and cultured cell B and pouring solution of composition A over cultured cell B would be bringing solution of composition A in contact with cell culture B.
  • Contacting a cell with a molecule would be bringing a molecule to the cell to ensure the cell have access to the molecule.
  • a cell can be brought into contact with a marker or a molecule, a biosensor, and so forth.
  • control or "control levels” or “control cells” or like terms are defined as the standard by which a change is measured, for example, the controls are not
  • 6vl subjected to the experiment are instead subjected to a defined set of parameters, or the controls are based on pre- or post-treatment levels. They can either be run in parallel with or before or after a test run, or they can be a pre-determined standard.
  • a control can refer to the results from an experiment in which the subjects or objects or reagents etc are treated as in a parallel experiment except for omission of the procedure or agent or variable etc under test and which is used as a standard of comparison in judging experimental effects, Thus, the control can be used to determine the effects related to the procedure or agent or variable etc.
  • a test molecule on a cell For example, if the effect of a test molecule on a cell was in question, one could a) simply record the characteristics of the cell in the presence of the molecule, b) perform a and then also record the effects of adding a control molecule with a known activity or lack of activity, or a control composition (e.g., the assay buffer solution (the vehicle)) and then compare effects of the test molecule to the control.
  • a control composition e.g., the assay buffer solution (the vehicle)
  • aryl as used herein is a ring radical containing 6 to 1 8 carbons, or preferably 6 to 12 carbons, comprising at least one aromatic residue therein. Examples of such aryl radicals include phenyl, naphthyl, and ischroman radicals.
  • aryl as used throughout the specification and claims is intended to include both “unsubstituted alky Is" and “substituted alkyls", the later denotes an aryl ring radical as defined above that is substituted with one or more, preferably 1 , 2, or 3 organic or inorganic substituent groups, which include but are not limited to a halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, amino, mono-substituted amino, di- substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonato, sulfamoyl, sulfonamide, azido acyloxy, nitro, cyano, carboxy, car- boalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido
  • arylalkyl An aryl moiety with 1 , 2, or 3 alkyl substituent groups can be referred to as "arylalkyl.”It will be understood by those skilled in the art that the moieties substituted on the "aryl” can themselves be substituted, as described above, if appropriate.
  • heteroatom refers to an atom of an element other than carbon or hydrogen.
  • heteroaryl as used herein is an aryl ring radical as defined above, wherein at least one of the ring carbons, or preferably 1 , 2, or 3 carbons of the aryl aromatic ring has been replaced with a heteroatom, which include but are not limited to nitrogen, oxygen, and sulfur atoms.
  • heteroaryl residues include pyridyl, bipyridyl, furanyl, and thiofuranyl residues.
  • Substituted "heteroaryl” residues can have one or more organic or inorganic substituent groups, or preferably 1 , 2, or 3 such groups per ring, as referred to herein-above for aryl groups, bound to the carbon atoms of the heteroaromatic rings.
  • the organic substituent groups can comprise from
  • heterocyclyl or “heterocyclic group” as used herein is a non- aromatic mono- or multi ring radical structure having 3 to 16 members, preferably 4 to 10 members, in which at least one ring structure include 1 to 4 heteroatoms (e.g. O, N, S, P, and the like).
  • Heterocyclyl groups include, for example, pyrrolidine, benzo- dioxoles, oxolane, thiolane, imidazole, oxazole, piperidine, piperizine, morpholine, lactones, such as thiobutyrolactones, lactams, such as azetidiones, and pyrrolidines, sultams, sultones, and the like.
  • heterocyclyl as used throughout the specification and claims is intended to include both unsubstituted heterocyclyls and substituted heterocyclyls; the latter denotes a ring radical as defined above that is substituted with one or more, preferably 1 , 2, or 3 organic or inorganic substituent groups, which include but are not limited to a halogen, alkyl, alkenyl, alkynyl, hy- droxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonato, sulfa- moyl, sulfonamide, azido acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarbox- amido, substituted alkylcarboxamido, dial
  • organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "heterocy- clyl" can themselves be substituted, as described above, if appropriate,
  • carrier refers to a cyclic moiety in which all members forming the ring are carbon atoms.
  • alkyl refers to a branched or unbranched saturated hydrocarbon moiety, which may optionally be cyclical or contain a cyclical portion. Alkyls comprise a saturated hydrocarbon moiety having from 1 to 24 carbons, 1 to 20 carbons, 1 to 15 carbons, 1 to 12 carbons, 1 to 8 carbons, 1 to 6 carbons, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. It is understood that the term “alkyl” also encompasses linear, branched or cyclic hydrocarbon moieties having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 carbon atoms.
  • alkyl radicals examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, rt-propyl, wo-propyl, cyclopropyl, butyl, «-butyl, sec-butyl, /-butyl, cyclobutyl, amyl, /-amyl, rc-pentyl, cyclopentyl, and the like.
  • Lower alkyls comprise a noncyclic, saturated, straight or branched chain hydrocarbon residue having from 1 to 4 carbon atoms, i.e., C1-C4 alkyl.
  • alkyl as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”; the latter denotes an alkyl radical analogous to the above definition, that is further substituted with one, two, or more additional organic or inorganic substituent groups.
  • Suitable substituent groups include but are not limited to H, alkyl, alkenyl, alkynyl, hydroxy], cycloalkyl, heterocyclyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonato, sulfamoyl, sulfonamide, azido, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcar- boxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcar- boxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkoxy, heteroaryl, substituted heteroaryl,
  • 6V 1 carbonyl substituted "alkyl” forming an ester When more than one substituent group is present then they can be the same or different.
  • the organic substituent moieties can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "alkyl" chain can themselves be substituted, as described above, if appropriate.
  • alkenyl as used herein is an alkyl residue as defined above that also comprises at least one carbon-carbon double bond in the backbone of the hydrocarbon chain. Examples include but are not limited to vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like.
  • alkenyl includes dienes and trienes of straight and branch chains.
  • alkynyl as used herein is an alkyl residue as defined above that comprises at least one carbon-carbon triple bond in the backbone of the hydrocarbon chain. Examples include but are not limited ethynyl, 1 -propynyl, 2-propynyl, 1 - butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 - hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • alkynyl includes di- and tri-ynes.
  • cycloalkyi is a saturated hydrocarbon structure wherein the structure is closed to form at least one ring.
  • Cycloalkyls typically comprise a cyclic radical containing 3 to 8 ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.
  • Cycloalkyi radicals can be multicyclic and can contain a total of 3 to 1 8 carbons, or preferably 4 to 12 carbons, or 5 to 8 carbons. Examples of multicyclic cycloalkyls include decahydronapthyl, adamantyl, and like radicals.
  • cycloalkyi as used throughout the specification and claims is intended to include both “unsubstituted cycloalkyls” and “substituted cycloalkyls”, the later denotes an cycloalkyi radical analogous to the above definition that is further substituted with one, two, or more additional organic or inorganic substituent groups that can include but are not l imited to hydroxyl, cycloalkyi, amino,
  • cycloalkenyl as used herein is a cycloalkyl radical as defined above that further comprises at least one carbon-carbon double bond. Examples include but are not limited to cyclopropenyl, 1 -cyclobutenyl, 2-cyclobutenyl, 1 - cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1 -cyclohexyl, 2-cyclohexyl, 3- cyclohexyl and the like.
  • hydrocarbon moiety refers to hydrocarbons, saturated or unsaturated, linear or branched or cyclic, substituted or unsubstituted, having up to eight carbons.
  • alkoxy refers to an alkyl residue, as defined above, bonded directly to an oxygen atom, which is then bonded to another moiety. Examples include methoxy, ethoxy, rc-propoxy, /so-propoxy, «-butoxy, f-butoxy, iso- butoxy and the like.
  • lower alkoxy refers to an alkoxy residue having up to eight carbons in the alkyl radical.
  • amino as used herein is a moiety comprising a N radical substituted with zero, one or two organic substituent groups, which include but are not limited to alkyls, , substituted alkyls, cycloalkyls, aryls, or arylalkyls. If there are two substituent groups they can be different or the same.
  • substituent groups include, -NH 2) methylamino (-NH-CH3); ethylamino (-NHCH 2 CH 3 ), hydroxyethyl- amino (-NH-CH 2 CH 2 OH), dimethylamino, methylethylamino, diethylamino, and the like.
  • mono-substituted amino as used herein is a moiety comprising an NH radical substituted with one organic substituent group, which include but are not limited to alkyls, substituted alkyls, cycioalkyls, aryls, or arylaikyis.
  • organic substituent group include but are not limited to alkyls, substituted alkyls, cycioalkyls, aryls, or arylaikyis.
  • Examples of mono-substituted amino groups include methylamino (-NH-CH3); ethylamino (- NHCH 2 CH 3 ), hydroxy ethylamino (-NH-CH 2 CH 2 OH), and the like.
  • di-substituted amino is a moiety comprising a nitrogen atom substituted with two organic radicals that can be the same or different, which can be selected from but are not limited to aryl, substituted aryl, alkyl, substituted alkyl or arylalkyl, wherein the terms have the same definitions found throughout. Some examples include dimethylamino, methylethylamino, diethylamino and the like.
  • acyl as used herein is a R-C(O)- residue having an R group containing 1 to 8 carbons.
  • acyl encompass acyl halide, R-(0)-halogen. Examples include but are not l imited to formyl, acetyl, propionyl, butanoyl, iso- butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, and natural or unnatural amino acids.
  • acyloxy as used herein is an acyl radical as defined above directly attached to an oxygen to form an R-C(0)0- residue. Examples include but are not limited to acetyloxy, propionyloxy, butanoyloxy, /so-butanoyloxy, benzoyloxy and the like.
  • azide refers to any moiety or compound comprising the monovalent group— N3 or the monovalent ion ⁇
  • benzo refers to a phenyl group that has in common with another moiety two neighboring carbon atoms that are bonded to one another.
  • these and like terms as used herein refer to the sharing of two neighboring phenyl ring carbons with another cyclic moiety
  • bridge refers to a cyclic moiety in which two atoms that are part of a covalent sequence of atoms are each bonded to the same substituent such that it defines a bridge between them, and such that together with the covalent sequence of atoms defines a cyclic moiety.
  • electronegative substituents such as: halides such as fluoride, chloride, and the like; pseudohalides such as cyanide, cy- anate, thiocyanate, and the like; nitro and nitroso groups and the like; sulfate groups, tosyl groups and the like; doubly bonded oxygen; and other highly electronegative substituents
  • haloalkyl as used herein an alkyl residue as defined above, substituted with one or more halogens, preferably fluorine, such as a trifluoromethyl, pen- tafluoroethyl and the like.
  • haloalkoxy refers to a haloalkyl residue as defined above that is directly attached to an oxygen to form trifluoromethoxy, penta- fluoroethoxy and the like.
  • halo or "halogen” or “halide” as used herein refers to a fluoro, chloro, bromo or iodo group.
  • any order refers to a linear series having a plurality of members, wherein the members may be arranged in any order relative to one another in the series.
  • linker refers to a covalently bonded sequence of from one to eight atoms, in which one end of the sequence is covalently bonded to a first moiety and the other end of the sequence is covalently bonded to a second moiety; the structures of the first and second moieties may be like or unlike one another.
  • a linker can for example comprise methylene groups, -S-, -0-, -N(R a )-, aryl, het- eroaryl, cycloalkyl, heterocyclyl.
  • the linker can comprise multiple groups of the same type, for example the linker can comprise 1 - 15 methylene groups.
  • moiety refers to part of a molecule (or compound, or analog, etc.).
  • a “functional group” is a specific group of atoms in a molecule.
  • a moiety can be a functional group or can include one or more functional groups.
  • esters as used herein is represented by the formula— C(0)OA, where A can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyi, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • carbonate group as used herein is represented by the formula -OC(0)OR, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyi, halogenated alkyl, or heterocycloalkyl group described above.
  • keto group as used herein is represented by the formula - C(0)R, where R is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyi, halogenated alkyl, or heterocycloalkyl group described above.
  • aldehyde as used herein is represented by the formula - C(0)H or -R-C(0)H, wherein R can be as defined above alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyi, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ether as used herein is represented by the formula AOA 1 , where A and A 1 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroary l, cycloalkyi, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • urethane as used herein is represented by the formula -OC(0)NRR', where R and R' can be, independently, hydrogen, an alkyl, alkenyl, al- kynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • methylene refers to a carbon atom in series -C(R)(R')- wherein R and R' can be, independently, hydrogen, a lower hydrocarbon moiety, an electron withdrawing group, aryl, aralkyl, alkaryl, halogenated alkyl, alkoxy, heteroaryl or heterocycloalkyl group described above. In particular embodiments R and R' are selected from hydrogen and unsubstituted lower hydrocarbon moieties.
  • silica group as used herein is represented by the formula -SiRR'R", where R, R', and R" can be, independently, hydrogen, an alkyl, alkenyl, al- kynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy, or heterocycloalkyl group described above.
  • sulfo-oxo group as used herein is represented by the formulas -S(0) 2 R, -OS(0) 2 R, or , -OS(0) 2 OR, where R can be hydrogen or as defined above an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • a compound for use in the invention may form a complex such as a
  • clathrate a drug-host inclusion complex, wherein, in contrast to solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • a compound used herein can also contain two or more organic and/or inorganic components which
  • 6V I can be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes can be ionised, partially ionised, or non-ionised.
  • Detect or like terms refer to an ability of the apparatus and methods of the disclosure to discover or sense a molecule- or a substance-induced response (i.e. cellular) and to distinguish the sensed responses for distinct molecules.
  • a "direct action” or like terms is a result (of a drug candidate molecule") acting independently on a cell.
  • a drug candidate molecule or like terms is a test molecule which is being tested for its ability to function as a drug or a pharmacophore. This molecule may be considered as a lead molecule.
  • Efficacy or like terms is the capacity to produce a desired size of an effect under ideal or optimal conditions. It is these conditions that distinguish efficacy from the related concept of effectiveness, which relates to change under real-life conditions. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.
  • basal levels are normal in vivo levels prior to, or in the absence of, or addition of a molecule such as an agonist or antagonist to a cell.
  • Inhibit or forms of inhibit or like terms refers to to reducing or suppressing.
  • a known molecule or like terms is a molecule with known pharma- cological/biological/physiological/pathophysiological activity whose precise mode of action(s) may be known or unknown. .
  • a ligand or like terms is a substance or a composition or a molecule that is able to bind to and form a complex with a biomolecule to serve a biological purpose. Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems.
  • Ligand binding to receptors alters the chemical conformation, i.e., the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of the receptor. The tendency or strength of binding is called affinity.
  • Ligands include substrates, blockers, inhibitors, activators, and neurotransmitters.
  • Radioligands are radioisotope labeled ligands, while fluorescent ligands are fluorescently tagged ligands; both can be considered as ligands are often used as tracers for receptor biology and biochemistry studies. Ligand and modulator are used interchangeably.
  • Material is the tangible part of something (chemical, biochemical, biological, or mixed) that goes into the makeup of a physical object.
  • molecule refers to performing one or more of the functions of a reference object. For example, a molecule mimic performs one or more of the functions of a molecule.
  • To modulate, or forms thereof, means either increasing, decreasing, or maintaining a cellular activity mediated through a cellular target. It is understood that wherever one of these words is used it is also disclosed that it could be 1 %, 5%, 10%, 20%, 50%, 100%, 500%, or 1000% increased from a control, or it could be 1 %, 5%, 10%, 20%, 50%, or 100% decreased from a control.
  • a modulator or like terms is a ligand or molecule that controls the activity of a cellular target. It is a signal modulating molecule binding to a cellular target, such as a target protein.
  • molecule refers to a biological or biochemical or chemical entity that exists in the form of a chemical molecule or molecule with a definite molecular weight.
  • a molecule or like terms is a chemical, biochemical or biological molecule, regardless of its size.
  • molecules are of the type referred to as organic molecules (molecules containing carbon atoms, among others, connected by covalent bonds), although some molecules do not contain carbon (including simple molecular gases such as molecular oxygen and more complex molecules such as some sulfur-based polymers).
  • the general term "molecule” includes numerous descriptive classes or groups of molecules, such as proteins, nucleic acids, carbohydrates, steroids, organic pharmaceuticals, small molecule, receptors, antibodies, and lipids.
  • a molecule mixture or like terms is a mixture containing at least two molecules.
  • the two molecules can be, but not limited to, structurally different (i.e., enantiomers), or compositional!y different (e.g., protein isoforms, glycoform, or an antibody with different poly(ethylene glycol) (PEG) modifications), or structurally and compositionally different (e.g., unpurified natural extracts, or unpurified synthetic compounds).
  • structurally different i.e., enantiomers
  • compositional!y different e.g., protein isoforms, glycoform, or an antibody with different poly(ethylene glycol) (PEG) modifications
  • structurally and compositionally different e.g., unpurified natural extracts, or unpurified synthetic compounds.
  • Molecule pharmacology or the like terms refers to the systems cell biology or systems cell pharmacology or mode(s) of action of a molecule acting on a
  • the molecule pharmacology is often characterized by, but not limited, toxicity, ability to influence specific cellular process(es) (e.g., proliferation, differentiation, reactive oxygen species signaling), or ability to modulate a specific cellular target (e.g., p75NTR with NGF or pro-NGF).
  • specific cellular process(es) e.g., proliferation, differentiation, reactive oxygen species signaling
  • a specific cellular target e.g., p75NTR with NGF or pro-NGF
  • nervous system has its usual and ordinary meaning in anatomy, and encompasses the entire nervous system, including but not limited to peripheral nerve cells, the central nervous system, and the brain.
  • composition can comprise a combination
  • the composition may comprise a combination of different molecules or may not include a combination such that the description includes both the combination and the absence of the combination (i.e., individual members of the combination).
  • pharmaceutically effective amount refers to an amount of medicinal composition sufficient to provide IC50 p75/NGF biological activity at a concentration below 5000 nM.
  • a "positive control” or like terms is a control that shows that the conditions for data collection can lead to data collection.
  • “Potency” or like terms is a measure of molecule activity expressed in terms of the amount required to produce an effect of given intensity. For example, a highly potent drug evokes a larger response at low concentrations. The potency is proportional to affinity and efficacy. Affinity is the ability of the drug molecule to bind to a receptor.
  • Prodrug or the like terms refers to compounds that when metabolized in vivo, undergo conversion to compounds having the desired pharmacological activity.
  • Prodrugs may be prepared by replacing appropriate functionalities present in pharmacologically active compounds with "pro-moieties" as described, for example, in H. Bundgaar, Design of Prodrugs (1985).
  • Examples of prodrugs include ester, ether or amide derivatives of the compounds herein, and their pharmaceutically acceptable salts.
  • prodrugs see e.g., T. Higuchi and V. Stella "Pro-drugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).
  • a receptor or like terms is a protein molecule embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling (or "signal") molecule may attach.
  • a molecule which binds to a receptor is called a "ligand,” and may be a peptide (such as a neurotransmitter), a hormone, a pharmaceutical drug, or a toxin, and when such binding occurs, the receptor goes into a conformational change which ordinarily initiates a cellular response.
  • some ligands merely block receptors without inducing any response (e.g. antagonists).
  • Ligand-induced changes in receptors result in physiological changes which constitute the biological activity of the ligands.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antece-
  • a response or like terms is any reaction to any stimulation.
  • sample or like terms is meant an animal, a plant, a fungus, etc.; a natural product, a natural product extract, etc.; a tissue or organ from an animal; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g. a polypeptide or nucleic acid), which is assayed as described herein.
  • a sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt
  • 6V I of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of formula I or II with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • the salts of the compounds of this invention are nontoxic "pharmaceutically acceptable salts.” Salts encompassed within the term
  • “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate,
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( - methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( - methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrC 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • lower alkyl (CrC 6 ) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates i.e., dimethyl, die
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compounds of the invention and their salts may exist in both unsolvated and solvated forms.
  • the compounds herein, and the pharmaceutically acceptable salts thereof may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may also exist in unsolvated and solvated forms.
  • solvate describes a molecular complex comprising the compound and one or more
  • solvent molecules e.g., EtOH
  • hydrate is a solvate in which the solvent is water.
  • Pharmaceutically acceptable solvates include
  • 6V I those in which the solvent may be isotopically substituted (e.g., D 2 0, d 6 -acetone, d 6 - DMSO).
  • Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound.
  • the solvent e.g., water
  • the solvent molecules lie in lattice channels where they are next to other solvent molecules.
  • metal-ion coordinated solvates the solvent molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds herein, and the pharmaceutically acceptable salts thereof may also exist as multi- component complexes (other than salts and solvates) in which the compound and at least one other component are present in stoichiometric or non-stoichiomethc amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non- covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O.
  • stable or like terms is generally understood in the art as meaning less than a certain amount, usually 10%, loss of the active ingredient under specified storage conditions for a stated period of time. The time required for a composition to be considered stable is relative to the use of each product and is dictated by the commercial practicali-
  • 6V I ties of producing the product, holding it for quality control and inspection, shipping it to a wholesaler or direct to a customer where it is held again in storage before its eventual use.
  • the minimum product life for pharmaceuticals is usually one year, and preferably more than 18 months.
  • stable references these market realities and the ability to store and transport the product at readily attainable environmental conditions such as refrigerated conditions, 2°C to 8°C.
  • a substance or like terms is any physical object.
  • a material is a substance. Molecules, ligands, markers, cells, proteins, and DNA can be considered substances. A machine or an article would be considered to be made of substances, rather than considered a substance themselves.
  • the subject can include, for example, domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) and mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, etc.
  • mammals non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal.
  • the subject is a mammal such as a primate or a human.
  • the subject can be a non-human.
  • test molecule or like terms is a molecule which is used in a method to gain some information about the test molecule.
  • a test molecule can be an unknown or a known molecule.
  • Treating or treatment or like terms can be used in at least two ways. First, treating or treatment or like terms can refer to administration or action taken towards a subject. Second, treating or treatment or like terms can refer to mixing any two things together, such as any two or more substances together, such as a molecule and a cell. This mixing will bring the at least two substances together such that a contact between them can take place.
  • treating or treatment or like terms when treating or treatment or like terms is used in the context of a subject with a disease, it does not imply a cure or even a reduction of a symptom for example.
  • therapeutic or like terms when used in conjunction with treating or treatment or like terms, it means that the symptoms of the underlying disease are reduced, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced. It is understood that reduced, as used in this context, means relative to the state of the disease, including the molecular state of the disease, not just the physiological state of the disease.
  • a trigger or like terms refers to the act of setting off or initiating an event, such as a response.
  • tumor has its usual and ordinary meaning in oncology.
  • compositions, apparatus, and methods of the disclosure include those having any value or any combination of the values, specific values, more specific values, and preferred values described herein.
  • compositions, articles, and machines can be combined in a manner to comprise, consist of, or consist essentially of, the various components, steps, molecules, and composition, and the like, discussed herein. They can be used, for example, in methods for characterizing a molecule including a ligand as defined herein; a method of producing an index as defined herein; or a method of drug discovery as defined herein.
  • An unknown molecule or like terms is a molecule with unknown bio- logical/pharmacological/physiological/pathophysiological activity, but with known or unknown chemical structure.
  • a p75 NTR inhibitor and the like terms is a molecule, compound or composition that binds to p75 NTR .
  • a p75 NTR inhibitor can reduce, decrease, or inhibit
  • Angiogenesis inhibitor N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • An angiogenesis inhibitor or the like terms is a molecule, compound or composition that reduces, decreases or inhibits angiogenesis.
  • Optimizing refers to a process of making better or checking to see if it something or some process can be made better.
  • Therapeutic efficacy refers to the degree or extent of results from a treatment of a subject.
  • a toxicity marker is any reagent, molecule, substance etc. that can be used for identifying, diagnosing, prognosing a level of toxicity of a substance, in, for example, an organism or cell or tissue or organ.
  • An analytical method is, for example, a method which measures a molecule or substance.
  • gas chromatography, gel permeation chromatography, high resolution gas chromoatography, high resolution mass spectrometry, or mass spectrometry is analytical methods.
  • Toxicity is the degree to which a substance, molecule, is able to damage something, such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molecule.
  • something such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molecule.
  • the liver, or cells in the liver, hepatocytes can be damaged by certain substances.
  • X can be hydrogen, lower alkyl, haloalkyl or an electron withdrawing group
  • R 1 and R 3 can either both present or both absent, and
  • R 1 and R 3 if R 1 and R 3 are present then each can independently be unsubstituted lower alkyl, alkyl, halide and optionally together form a bridge, R 2 and R 4 can each be double bonded O, and Z' and Z 2 can each be an N bearing no double bonds; and r if R 1 and R 3 are absent then R 2 and R 4 can each be H or be double bonded O, the six- member ring can have 0-3 double bonds, Z 1 and Z 2 can independently be C or N, and the six-member ring if carbocyclic can optionally be substituted; if Z 1 and Z 2 are C then R 1 , R 2 , R 3 and R 4 can independently be present or absent, and if R 1 , R 2 , R 3 and R 4 are present then each can independently be H, halide, lower alkoxy, lower alkyl, hydroxyl or haloalkyl;
  • R 5 or R 6 can be present, can be bonded to a nitrogen atom having two single bonds in the five-member ring, and the other nitrogen atom in the five-member ring can be unsubstituted or substituted and bears a double bond in the ring, if R 5 or R 6 is bonded to a nitrogen that bears a double bond then R 5 or R 6 can be alkyl or halide, and R 5 or R 6 can be of the form -linker-R 7 , wherein
  • one or more of the methylene groups can optionally be substituted independently by a respective R b , wherein each R b can be lower alkyl and its identity can be independent of the identity
  • R a and a respective R b can together form a bridge; and R 7 can be an end group that can be: C
  • R 8 can be H, an electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, an optionally substituted fused benzo group, or
  • R if R is a triazole, then R can be optionally a six-member heteroaryl ring in which the heteroatoms can be 1 or 2 nitrogen atoms, and R 8 can optionally be substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy;
  • R 9 can be can be of the form -linker-R 7 , wherein
  • R a can be H or independently unsubstituted C1-C3,
  • one or more of the methylene groups can optionally be substituted independently by a respective R b , wherein each R b can be lower alkyl and its identity can be independent of the identity of R a and of respective R b on other methylene groups in the linker,
  • R a and a respective R b can together form a bridge
  • R 10 can be H or substituted or unsubstituted lower alkyl
  • each of R I S , R 16 , R 17 and R 18 can independently be H, an electron withdrawing group, lower alkyl, lower alkoxy, OH, or together forms a benzo substituent with a neighboring group
  • a and b can be hydrogen atoms bonded to the phenyl ring and c, respectively, but not to each other, or together a and b can form a bond; and g and h can be hydrogen atoms bonded to the phenyl ring and f, respectively, but not to each other, or together g and h can form a bond; wherein at least one of the pairs a-b and g-h is a bond;
  • R 19 and R 20 can have the form -linker-R 25 , and the other of R 19 and R 20 can be H, an electron withdrawing group, lower alkyl, lower alkoxy, OH, or can be a pi bond to the carbon atom at e, wherein:
  • R is an end group that can be a lower hydrocarbon moiety.
  • R 6 and R 9 can independently be H
  • R a can be H or C 1 -C3 alkyl.
  • n and m can independently be 1 , 2, 3 or 4.
  • o can be 1 , 2 or 3.
  • R 1 and R 3 can independently be H, C1-C3 alkyi, C1-C3 alkoxy, F, CI, hydroxyl, CF3. In another embodiment R 1 and R 3 can independently be H or CH3.
  • R 7 can be C
  • R 7 can be C1-C3 alkyl.
  • R 8 can be H, C1-C3 alkyl, C1-C3 alkoxy, halide,
  • R 10 can be H, halide, C1-C3 alkyl or branched C3-C6 alkyl. In some embodiments R 10 can be CH3.
  • R 1 1 can be H, C
  • R 12 can be H, C1-C6 alkyl, Ci-C 6 alkoxy, hal- ide or hydroxyl.
  • R can be R .
  • R 14 can be H, C
  • structure III can be
  • R can be H, C1-C3 alkyi or halide.
  • R 20 can be H, C1 -C3 alkyi or halide.
  • R 19 can be R configuration and R 20 can be S configuration
  • R 19 can be S configuration and R 20 can be R configuration.
  • R can be R configuration and the linker can be S configuration.
  • R 7 can be S configuration and the linker can be R configuration.
  • R 1 and R 3 can each be absent.
  • R 1 and R 3 can each be methyl or together form an ⁇ , ⁇ -propadiyl, ⁇ , ⁇ -butadiyl, or ⁇ , ⁇ -pentadiyl bridge.
  • Z' can be C and Z 2 can be N.
  • Z 1 can be N and Z 2 can be C.
  • Z 1 can be C and Z 2 can be C.
  • Z 1 can be N and Z 2 can be N.
  • R a and a respective R b together can form an al- kyl bridge defining a piperidinediyl ring in the linker.
  • composition can comprise structure I or II.
  • R 16 can be F and R 15 , R 17 and R 18 can each be
  • R 15 and R 16 can together form a benzo group, or R l 7 and R 18 can together form a benzo group.
  • the pair a and b and the pair g and h, one the of the pairs can be a bond and each member of the other pair can be a hydrogen atom.
  • e can be -(CH2) n - and n can be 1 -4.
  • a double bond can be present between e and f.
  • f can be chiral and can be substituted by H, an electron withdrawing group, lower alkyl, lower alkoxy, or OH.
  • R 2S can be an end group that can be i-propyl, s- butyl, 3-pentyl, or C3-C6 cycloalkyl.
  • a pharmaceutical composition comprising the compound of structure 111.
  • X can be hydrogen, lower alkyl, haioalkyl or an electron withdrawing group
  • R a can be H or independently unsubstituted C1-C3;
  • V 1 wherein n and m can independently be 1 , 2, 3 or 4
  • R 7 can be an end group that can be: C
  • R can be H, an electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, an optionally substituted benzo group, substituted fused benzo group, or
  • R 8 can optionally be a six-member heteroaryl ring in which the heteroatoms is 1 or 2 nitrogen atoms, and R 8 is optionally be substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy,
  • R 11 can be H, C
  • R 12 can be H, C
  • R 8 can be H, C1-C3 alkyl, C1-C3 alkoxy, halide, hydroxy I,
  • R ,2 can be H, C1-C6 alkyl, C1-C6 alkoxy, halide or hydroxyl
  • R M can be H, C ⁇ -Ce alkyl, C1-C6 alkoxy, halide or hydroxyl.
  • R 3 can be
  • Also disclosed herein is a method comprising administering to a subject in need of inhibition of a p75 neurotrophic receptors (p75 NTR ) a composition comprising a compound of any one of claims 1 -64.
  • p75 NTR p75 neurotrophic receptors
  • the subject can be suffering from or at risk for a disease associated with p75 NTR .
  • the subject can be diagnosed with a disease associated with p75 NTR .
  • the disease can be cancer.
  • the cancer can be brain cancer.
  • the brain cancer can be Glioblastoma multiforme.
  • the subject can be monitored for p75 NTR expression
  • the inhibition of p75 NTR can inhibit glioma invasion.
  • composition can further comprise a known p75 NTR inhibitor.
  • the method can prevent or treat a disease associated with p75 NTR .
  • Also disclosed herein is a method comprising administering to a subject in need of inhibition of angiogenesis a composition comprising a compound of any one of structure I, II or III.
  • the subject can be suffering from or at risk for a disease associated with angiogenesis.
  • the subject can be diagnosed with a disease associated with angiogenesis.
  • composition can further comprise a known angiogenesis inhibitor.
  • the method can prevent or treat a disease associated with angiogenesis.
  • the disease or disorder associated with angiogenesis can be selected from: tumor or cancer growth (neoplasia), skin disorders, neovascularization, inflammatory and arthritic diseases, retinoblastoma, cystoid macular edema (CME), exudative age- related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, or ocular inflammatory disorders.
  • the disease or disorder associated with angiogenesis can be a tumor or cancer growth (neoplasia).
  • the tumor or cancer growth is ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, corpus uteri, ovary cancer, prostate cancer, testicular cancer, renal cancer, brain/ens cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma,
  • hemangioendothelioma Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangiomas, and lymphangiogenesis .
  • the disease or disorder associated with angiogenesis can be a skin disorder.
  • the skin disorder can be psoriasis, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis, Sturge- Weber syndrome, venous ulcers of the skin, neurofibromatosis, and tuberous sclerosis.
  • the disease or disorder associated with angiogenesis is neovascularization.
  • the neovascularization can be diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjogren's, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoan infections, Kaposi's sarcoma,
  • Stevens- Johnson disease pemphigoid, radial keratotomy, corneal graft rejection, macular edema, macular degeneration, sickle cell anemia, sarcoid, syphilis,
  • 6V 1 pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications, and diseases associated with rubeosis (neovascularization of the ankle).
  • the disease or disorder associated with angiogenesis can be an inflammatory and arthritic disease.
  • the inflammatory and arthritic disease can be: rheumatoid arthritis, osteoarthritis, lupus, scleroderma, Crohn's disease, ulcerative colitis, psoriasis, sarcoidosis, Sarcoidosis, skin lesions, hemangiomas, Osier- Weber-Rendu disease, hereditary hemorrhagic telangiectasia, and osteoarthritis.
  • the disease or disorder can affect the dermis, epidermis, endometrium, retina, surgical wound, gastrointestinal tract, umbilical cord, liver, kidney, reproductive system, lymphoid system, central nervous system, breast tissue, urinary tract, circulatory system, bone, muscle, or respiratory tract.
  • the methods provide a method of preventing and treating tumors of the nervous system, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition that inhibits p75 neurotrophic receptors and prevents the spread of tumors in healthy nervous tissue, wherein the composition comprises a compound or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof having the formula:
  • R a can H or independently unsubstituted lower alkyl
  • one or more of the methylene groups if present can be optionally substituted independently by a respective R b , wherein each R b can be lower alkyl, heteroaryl, or optionally substituted phenyl, and the identity of each R b can be independent of the identity of R a and of respective R b on other methylene groups in the linker; and
  • R a and a respective R b can together form a bridge
  • I can be an end group that can be: a Ci-Cio hydrocarbon moiety; C3- C10 aryl, C3-Cio cycloalkyl, C3-C9 heterocyclic; optionally substituted indenyl; optionally substituted phenyl; or a 5- or 6- member heteroaryl ring having up to three heteroatoms selected from O, N and S, wherein the heteroaryl ring can optionally bear a substituent J; and wherein
  • J can bean electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, optionally substituted phenyl, or can optionally be substituted fused benzo group, or
  • J can optionally be a six-member heteroaryl ring in which the heteroatoms are 1 or 2 nitrogen atoms, and J is optionally substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy.
  • the methods provides a method of treating a disease or disorder associated with angiogenesis in a subject, the method comprising the step of administering to the subject an effective amount of a composition com- prises a compound or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof having the formula:
  • G can be an aryl, heteroaryl, cycloalkyl or heterocyclic residue selected from the group consisting of monocyclic and bicyclic ring systems, wherein G can optionally bear one or more substituents selected from electron withdrawing
  • R a can H or independently unsubstituted lower alkyf
  • one or more of the meth lene groups if present can be optionally substituted independently by a respective R b , wherein each R b can be lower alkyl, heteroaryl, or optionally substituted phenyl, and the identity of each R b can be independent of the identity of R a and of respective R b on other methylene groups in the linker; and
  • R a and a respective R b can together form a bridge
  • I can be an end group that can be: a C
  • J can bean electron withdrawing group, lower hydrocarbon moiety, lower alkoxy, optionally substituted phenyl, or can optionally be substituted fused benzo group, or
  • J can optionally be a six-member heteroaryl ring in which the heteroatoms are 1 or 2 nitrogen atoms, and J is optionally substituted at one or more carbon atoms on the ring by an electron withdrawing group, lower hydrocarbon moiety, or lower alkoxy.
  • I 250 can be Ci-Ce alkyl, C
  • all methods described herein can use a pharmaceutically effective amount of a composition that inhibits p75 neurotrophic receptors and prevents the spread of tumors in healthy nervous tissue, wherein the composition comprises any compound from structures I, II or III.
  • the gene coding for p75 was inserted into the bait vector pEG202 to express a fusion protein with the E.coli LexA DNA-binding protein.
  • the genes coding for the proteins eg. Pro-NGF
  • Pro-NGF proteins which interacts with p75 NTR is then subcloned in the target plasmid pJG4-5 to form a gene fusion with the bacterial acid blob domain B42.
  • LexA bound upstream of a reporter gene nor B42 alone can activate transcription of a reporter.
  • LEXA and B42 are brought together via fusions with two interacting proteins, reporter gene expression can be detected. Two reporter genes were employed.
  • the first gene lacZ contained on the reporter plasmid pSH 18-38 under the control of 8 LexA operators.
  • the expression of ⁇ -galactosidase can easily be monitored on medium containing X-Gal.
  • the second reporter- LEU2 is in the genome of the yeast S.cerevisiae host strain EGY48, genetically altered to be under the control of 6 LexA operators. When activated the reporter allows the EGY48 strain to grow on a selective medium without leucine.
  • EGY48 is also auxotrophic for histidine, uracil and tryptophan which allows for selection of clones stably transformed with the bait vector EG202, lacZ reporter plasmid pSH 1 8- 34 and target plasmid pJG4-5, respectively.
  • the dependence of activation of the reporter genes on the interaction between bait and target can be confirmed in this system due to the nutritional control of the expression of the B42-target protein fusion. It is activated on medium containing galactose as source of carbon and repressed on medium with glucose.
  • the low affinity neurotrophin receptor p75 is a multifunctional receptor with important roles in neurotrophin signaling, axon outgrowth, and is an important in signalling survival of oligodendroglia and neurons. It is transcriptionally regulated with spatial and temporal precision during nervous system development, injury and regeneration.
  • the p75 gene expression is directly modulated by the early growth response (Egr) transcriptional activators, Egrl and Egr3, which bind and trans- activate the p75 promoter in vitro and in vivo.
  • Egr early growth response
  • A. Develop and select the optimal p75 NTR inhibitors (modulators or gamma secretase inhibitors) using in vitro high throughput assays.
  • p75 NTR modulators can be derived from the small molecule librariesand known gamma secretase inhibitors and screened in a high throughput assay. These will be screened for activity in vitro for inhibition of p75 NTR in glioma lines and BTSCs derived from surgical specimens. The best compounds will then be further evaluated in B.
  • the toxicity and efficacy of the selected p75 NTR inhibitors will be determines using in vivo models of invasive gliomas and BTSCs. The dose will be optimized of the compunds, then their route of administration and their MTD in immunocompromised and immunocompetent rodents will be determined. Fluorescently labeled invasive clones will be used from U87 and U251N, GL261 and p75 NTR expressing and non-expressing BTSCs. Proliferation, tumor size, invasion/metastases and survival will be assessed using conventional measures and via imaging with our 9.4T animal MRI. The best compounds will then be evaluated forr invasive glioma and BTSCs in vivo in C.
  • the toxicity and efficacy of combination therapy will be determined in in vitro and in vivo models of invasive gliomas and BTSCs.
  • the prevalence of p75 NTR expression will be determined from clinically available biopsy specimens of remotely invasive tumors in patients taking bevacizumab.
  • the toxicity and efficacy of combination therapy (p75 NTR inhibitor & bevacizumab) will be determined using approaches described elsewhere herein (and assessing markers of angiogenesis).
  • the combination therapy will be determined that inhibit the invasive phenotype arising when bevacizumab is combined with p75 NTR inhibitors using invasive glioma clones and BTSCs.
  • the molecules and compound, including those used in methods described herein, can be synthesized using highly versatile synthetic chemistry reactions.
  • Molecules and compounds are typically synthesized using amide chemistry.
  • Amide can be made by reacting carboxylic acid with a primary amine by first activating the carboxylic acid to an acid chloride or an acyl chloride (using PC , PCI5, or similar re- actants), the acid chloride then reacts with the primary amine using conditions such as Schotten-Baumann conditions, such as water and diethyl ether.
  • Other synthetic routes include reacting a carboxylic acid with a primary amine using EDCI and DMAP, as shown below.
  • the amide chemistry is especially versatile because there are many
  • carboxylic acid can be synthesized from alcohols, aldehydes, alkenes, alkyls, ketones, nitriles etc.
  • amines can be synthesized from nitriles, azides, noranesm carbamates, lactams etc.
  • compound A can be made using the following synthesis:
  • compound B can be made using the following synthesis:
  • Inhibiting angiogenesis is a potential therapeutic target in MGs.
  • compound A were also assessed in vitro and in vivo co-cultures of microvascular endothelial cells and invasive gliomas (U87p75+, U87R) for vascular branch-
  • HBMEC Human Brain Microvascular Endothelial Cell
  • BTIC brain tumor initiating cells
  • the cell/matrix mix was placed in a transwell filter unit and incubated for 1 hr at 37 °C to solidify the matrix.
  • the transwell unit was then placed in 1 ml of serum containing media (with any appropriate drug) and 100 ul of serum-free media (with drug) was placed above the cell/matrix mix to create a chemotactic gradient.
  • the cells were allowed to invade through the matrix and filter for 6 hrs at 37 °C and the number of invading cells was quantified by staining the formalin fixed filters with DAPI and examination under a fluorescent microscope.

Abstract

L'invention concerne des composés, des compositions et des procédés de prévention et de traitement de tumeurs du système nerveux, au moyen de composés qui inhibent ou modulent les récepteurs de neurotrophines p75. Les composés de l'invention ont des structures de la forme G-H-I, dans laquelle G représente un petit système cyclique rappelant les fragments médiant les réactions redox dans le métabolisme, H représente un lieur de longueur allant jusqu'à 8 atomes, et I représente un groupe terminal simple comme un groupe alkyle inférieur ou un petit système cyclique hétéroarylique ou hétérocyclique.
PCT/US2011/039847 2010-06-09 2011-06-09 Compositions et procédés de traitement de tumeurs dans le système nerveux WO2011156632A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102643188A (zh) * 2012-05-09 2012-08-22 岳阳亚王精细化工有限公司 一种5-溴戊酸的制备方法
CN103360393A (zh) * 2013-07-29 2013-10-23 上海万巷制药有限公司 茶碱乙酸的制备方法
WO2014152013A1 (fr) * 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phénylpipéridines, leur préparation et leur utilisation
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
JP2016540803A (ja) * 2013-12-17 2016-12-28 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ Ｗｎｔ経路モジュレーター
WO2017015267A1 (fr) * 2015-07-20 2017-01-26 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10316040B2 (en) 2015-10-16 2019-06-11 Eisai R&D Management Co., Ltd. EP4 antagonists
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11530216B2 (en) 2020-12-23 2022-12-20 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060246072A1 (en) * 2005-04-15 2006-11-02 University Of North Carolina At Chapel Hill Methods of facilitating cell survival using neurotrophin mimetics
US20080139585A1 (en) * 2006-09-21 2008-06-12 Nova Southeastern University Specific inhibitors for vascular endothelial growth factor receptors
US20100061981A1 (en) * 2008-08-15 2010-03-11 The Salk Institute For Biological Studies p75NTR MEDIATES EPHRIN-A REVERSE SIGNALING

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060246072A1 (en) * 2005-04-15 2006-11-02 University Of North Carolina At Chapel Hill Methods of facilitating cell survival using neurotrophin mimetics
US20080139585A1 (en) * 2006-09-21 2008-06-12 Nova Southeastern University Specific inhibitors for vascular endothelial growth factor receptors
US20100061981A1 (en) * 2008-08-15 2010-03-11 The Salk Institute For Biological Studies p75NTR MEDIATES EPHRIN-A REVERSE SIGNALING

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US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
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CN103360393A (zh) * 2013-07-29 2013-10-23 上海万巷制药有限公司 茶碱乙酸的制备方法
JP2016540803A (ja) * 2013-12-17 2016-12-28 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ Ｗｎｔ経路モジュレーター
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
CN107922396A (zh) * 2015-07-20 2018-04-17 建新公司 集落刺激因子‑1受体(csf‑1r)抑制剂
RU2748884C2 (ru) * 2015-07-20 2021-06-01 Джензим Корпорейшн Ингибиторы рецептора колониестимулирующего фактора-1 (csf-1r)
WO2017015267A1 (fr) * 2015-07-20 2017-01-26 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
US11274108B2 (en) 2015-07-20 2022-03-15 Genzyme Corporation Colony stimulating factor-1 receptor (CSF-1R) inhibitors
JP2018524381A (ja) * 2015-07-20 2018-08-30 ジェンザイム・コーポレーション コロニー刺激因子−１受容体（ｃｓｆ−１ｒ）阻害剤
CN107922396B (zh) * 2015-07-20 2022-08-05 建新公司 集落刺激因子-1受体(csf-1r)抑制剂
US10941148B2 (en) 2015-10-16 2021-03-09 Eisai R&D Management Co., Ltd. EP4 antagonists
US10316040B2 (en) 2015-10-16 2019-06-11 Eisai R&D Management Co., Ltd. EP4 antagonists
US11434246B2 (en) 2015-10-16 2022-09-06 Eisai R&D Management Co., Ltd. EP4 antagonists
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11530216B2 (en) 2020-12-23 2022-12-20 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (CSF-1R) inhibitors
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

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