EP2403839A2 - Neurotrophin mimetics and uses thereof - Google Patents
Neurotrophin mimetics and uses thereofInfo
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- EP2403839A2 EP2403839A2 EP10749395A EP10749395A EP2403839A2 EP 2403839 A2 EP2403839 A2 EP 2403839A2 EP 10749395 A EP10749395 A EP 10749395A EP 10749395 A EP10749395 A EP 10749395A EP 2403839 A2 EP2403839 A2 EP 2403839A2
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Definitions
- the present application generally relates to compounds having a binding specificity for p75 NTR molecule and to the use of such compounds in the treatment of disorders involving degradation or dysfunction of cells expressing p75, including, for example neurodegenerative disorders.
- MBP myelin basic protein mg— milligram min ⁇ minute ml ⁇ milliliter mM—millimolar mol—mole
- NGF nerve growth factor
- nM nanomolar p ⁇ probability p75 TR ⁇ p75 neurotrophin receptor
- PBS phosphate-buffered saline pmol—picomole
- PVDF Polyvinylidine Difluoride
- Neurotrophins are polypeptides that play a role in the development, function, and/or survival of certain cells, including neurons, oligodendrocytes, Schwann cells, hair follicle cells, and other cells.
- the death or dysfunction of neurons and other cell types has been directly implicated in a number of neurodegenerative disorders. It has been suggested that alterations in neurotrophin localization, expression levels of neurotrophins, and/or expression levels of the receptors that bind neurotrophins are therefore linked to neuronal degeneration. Degeneration occurs in the neurodegenerative disorders Alzheimer's, Parkinson's and ALS, among others. Degeneration of oligodendrocytes can occur in central nervous system injury, multiple sclerosis, and other pathological states.
- Neurotrophins include Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5), Neurotrophin 6 (NT-6) and Brain Derived Neurotrophic Factor (BDNF).
- NGF Nerve Growth Factor
- NT-3 Neurotrophin-3
- NT-4/5 Neurotrophin-4/5
- NT-6 Neurotrophin 6
- BDNF Brain Derived Neurotrophic Factor
- Neurotrophins are found in both precursor form, known as pro-neurotrophins, and in mature form.
- the mature forms are proteins of about 120 amino acids in length that exist in physiological states as stable, non-covalent approximately 25 kDa homodimers.
- Each neurotrophin monomer includes three solvent-exposed ⁇ -hairpin loops, referred to as loops 1, 2, and 4 that exhibit relatively high degrees of amino acid conservation across the neurotrophin family.
- Mature neurotrophins bind preferentially to the receptors Trk and p75 NTR (p75 neurotrophin receptor, also called the Low Affinity Nerve Growth Factor Receptor or LNGFR) while pro-neurotrophins, which contain an N-terminal domain proteolytically removed in mature forms, interact principally with p75 and through their N-terminal domains, with the sorting receptor sortilin (Fahnestock, M., et al. (2001) MoI Cell Neurosci 18, 210-220; Harrington, A. W. et al. (2004) Proc Natl Acad Sci USA 101, 6226-6230; Nykiaer. A. et al., (2004) Nature 427, 843- 848).
- Trk and p75 NTR p75 neurotrophin receptor, also called the Low Affinity Nerve Growth Factor Receptor or LNGFR
- pro-neurotrophins which contain an N-terminal domain proteolytically removed in mature forms, interact principally with
- p75 NTR interacts with Trks and modulates Trk signaling, but is also independently coupled to several signaling systems, including pro-survival signals, IRAK/TRAF6/NF.kappa.B, PI3/AKT, and pro-apoptotic signals, NRAGE/JNK (Mamidipudi, V., et al. (2002) J Biol Chem 277, 28010-28018; Roux, P. P., et al. (2001) J Biol Chem 276, 23097-23104; Salehi, A. H., et al. (2000) Neuron 27, 279- 288).
- neurotrophins When administered for therapeutic use, neurotrophins exhibit suboptimal pharmacological properties, including poor stability with low serum half lives, likely poor oral bioavailability, and restricted central nervous system penetration (Podulso, J. F., Curran, G. L. (1996) Brain Res MoI Brain Res 36, 280-286; Saltzman, W. M., et al (1999) Pharm Res 16, 232-240; Partridge, W. M. (2002) Adv Exp Med Bio 513, 397-430). Additionally, the highly pleiotropic effects of neurotrophins achieved through action of the dual receptor signaling network increases the chances of adverse effects.
- This application generally discloses compounds having binding specificity for p75 NTR , as well as to methods for the preparation and use of such compounds, and to pharmaceutical compositions containing the same. More specifically, compounds of the present application are represented by the general structures:
- Y, Z m, n, p, q, r, s, t are as defined below.
- Figure Ia is a ribbon representation of the X-ray crystal structure of human NGF with ⁇ -turn loops 1, 2, and 4 designated. The average side chain positions for loop 1 are illustrated.
- Figure Ib represents the comparison of peptide sequences (SEQ ID NOs: 1-3) of loop 1 from NGF and NT3 from the indicated species and the assignment of pharmacophores. Positively ionizable groups are signified by "+”. "HBD” and “HBA” represent hydrogen bond donor and hydrogen bond acceptor, respectively.
- Figure Ic shows application of the pharmacophoric features to a 3D loop model.
- Hydrogen bonding features are represented by pairs of spheres with their relative positions indicating the locations of the acceptor and the donor. One of the spheres of the pair is centered on putative acceptor/donor features in the model, while the other indicates the target location of a complementary feature on any potentially interacting molecule.
- the diameter of the spheres represents the spatial tolerance for chemical feature matching in 3D conformer library scans.
- Figure Id is a 3D loop model disclosing representative fits to the pharmacophore of two compounds identified by application of the novel pharmacophore in library screening subsequently found to be active as disclosed herein.
- Figure 2a is a series of fluorescence photomicrographs of E16-17 mouse hippocampal neuronal cultures treated with culture medium only (CM) or medium containing BDNF or Compound (i) (referred to in the figures as “LMl 1 A-28” or “28"), Compound (ii) (referred to in the figures as “LM11A-7” or “7"), Compound (iii) (referred to in the figures as “LM11A-24” or “24”), Compound (iv) (referred to in the figures as “LM11A-31” or “31”), or Compound (v) (referred to in the figures as “LM11A-36” or “36”).
- CM culture medium only
- BDNF BDNF
- Figure 2b is a series of neuron survival dose-response curves of BDNF, NGF, and Compounds (i-v), showing similar potency and maximal responses between NGF and Compounds (i-iv) up to 5 nM, with no response to Compound (v).
- BDNF has similar potency, but a higher maximal response.
- Each of Compounds (i- v), show a decrementing response above 5 nM.
- Figure 3 a is a series of NGF/p75 NTR -Fc binding curves, in the presence of increasing concentrations of Compound (iv), as detected by NGF ELISA. Symbols are mean +/- s.e.m. n > 10 for all determinations. Lines represent fitting to a modified Gaddum/Schild equation, with an overall R value of 0.93 for Compound (iv). Also, PO.0001 by ANOVA with post-hoc Bonferroni/Dunn testing, for comparisons between binding curves at 0 nM compound and curves with > 500 nM Compound (iv).
- K D for NGF in the absence of compounds was 0.8-0.9 nM, consistent with previous reports of approximately 1 nM (Nykjaer, A. et al., (2004) Nature All, 843-848).
- the symbols "•”, “ w “, “a”, “0”, “A”, and “o” represent Compound (iv) concentrations of zero, 125, 500, 1,500, 4,500, and 10,000 nanomolar, respectively.
- Figure 3b is a series of NGF/p75 NTR -Fc binding curves, in the presence of increasing concentrations of Compound (iii), as detected by NGF ELISA. Symbols are mean +/- s.e.m. n > 10 for all determinations. Lines represent fitting to a modified Gaddum/Schild equation, with an overall R 2 value of 0.96 for Compound (iii). Also, P ⁇ 0.0001 by ANOVA with post-hoc Bonferroni/Dunn testing, for comparisons between binding curves at 0 nM compound and curves with > 125 nM Compound (iii).
- Figure 3 c is a series of NGF/TrkA-Fc binding curves in the presence of increasing concentrations of Compound (v), showing no significant effect up to 10,000 nM. Symbols are mean +/- s.e.m. n > 10 for all determinations. The symbols "•”, “ ⁇ 7 ", and "a”, represent Compound (v) concentrations of zero, 4,500, and 10,000 nanomolar, respectively.
- Figure 3d is a series of NGF/TrkA-Fc binding curves in the presence of increasing concentrations of Compound (iv) showing no compound effects up to 10,000 nM. Symbols are mean +/- s.e.m. n > 4 for all determinations. The symbols “ ⁇ ” ; “ ⁇ 7 " 5 and “ ⁇ ”, represent Compound (iv) concentrations of zero, 4,500, and 10,000 nanomolar, respectively.
- Figure 3e is a series of NGF/TrkA-Fc binding curves in the presence of increasing concentrations of Compound (iii) showing no compound effects up to 10,000 nM. Symbols are mean +/- s.e.m. n > 4 for all determinations. The symbols "•”, “ v ", and "a”, represent Compound (iii) concentrations of zero, 4,500, and 10,000 nanomolar, respectively.
- Figure 3f is a digital image of a western blot showing displacement of anti-p75 NTR Ab 9651 from anti-p75 NTR -expressing 3T3 cells by Compound (iv), but not Compound (v).
- the upper panel represents IgG heavy chain, the lower panel represents ⁇ -actin.
- a single asterisk (*) represents P ⁇ 0.0005, for comparison with binding in the absence of compound, by Student t-test. Antibody and compound treatments are designated above each lane.
- Ab 9651 did not bind to p75 NTR -negative cells (lanes 1 and 2).
- FIG. 3g is a bar graph showing that Ab 9651 has no effect on baseline survival (CM), partially inhibits BDNF, and completely inhibits Compound (iii) and Compound (iv) promotion of hippocampal neuron survival.
- the solid bars represent non-immune serum treatment.
- the shaded bars represent Ab 9651 treatment.
- the bars represent mean +/- s.e.m. n > 26 for each condition.
- Double asterisks (**) represent P ⁇ 0.00001 (for comparisons between Ab 9651 and non-immune).
- NS represents not significant by Student t-test. Survival in the presence of BDNF + Ab 9651 is shown to be significantly greater than CM + Ab 9651 (PO.00001), while the differences between CM and Compound (iii), Compound (iv), and Compound (v) in the presence of antibody are not significant.
- Figure 3h is a bar graph showing that p75 -deficiency partially inhibits BDNF and completely inhibits NGF, Compound (iii), and Compound (iv) promotion of hippocampal neuron survival.
- Neurotrophins were applied at 1.8 nM, and compounds at 5 nM.
- the solid bars represent p75 NTR+/+ cells.
- the shaded bars represent p75 NTR" " cells.
- the bars represent mean +/- s.e.m. n > 5 for each condition.
- the single asterisk (*) represents P ⁇ 0.05
- the double asterisk (**) represents P ⁇ 0.005.
- NS represents not significant (for comparisons between knockout and wild type) by Student t-test.
- FIG. 3i shows digital images of western blots of hippocampal neuron cultures using anti-phosphorylated Trk Y4 , compared with total TrkB. BDNF activated TrkB, while NGF and Compounds (iii-v) resulted in no detectable activation at 10 or 30 minutes.
- Figure 3j shows digital images of western blots of TrkA-expressing 3T3 cells using anti-phosphorylated Trk Y490 compared with total TrkA. NGF is shown to activate TrkA, while Compound (iv) produced no detectable activation. Results of two additional independent assays for TrkB and TrkA activation were identical.
- Figure 4a is a digital image of a western blot indicating NF ⁇ B-p65 activation analysis, showing similar activation kinetics for all biologically active treatments.
- Figure 4b is a digital image of a western blot representing AKT activation analysis, showing a small lag in activation by the active compounds relative to NGF.
- Figure 4c is a digital image of a western blot representing ERK44 activation analysis, showing less activation at 10 minutes for the compounds relative to NGF.
- Figure 4d is the digital image of a western blot representing ERK42 activation analysis, showing prolonged activation with BDNF treatment relative to NGF and Compounds (iii-v).
- Figure 4e is a bar graph indicating survival of hippocampal neurons in cultures treated with signaling pathway inhibitors and BDNF (25 ng/ml), NGF (25 ng/ml), or Compounds (iii-v) (5 nM), showing substantial inhibition by NFKB and Pl 3 K pathway inhibitors, small effects of ERK inhibition on BDNF and NGF activity, and no effect of ERK inhibition on the activity of Compounds (iii-v).
- SN50 is an NFKB translocation inhibitor.
- LY represents LY294002, a P13K inhibitor.
- PD represents PD98059, an ERK inhibitor.
- n 18 for each bar, showing mean + s.e.m.
- NS represents that the data is not significant.
- a single asterisk (*) indicates P ⁇ 0.05
- double asterisks (**) indicates that P ⁇ 0.001 for comparison with control (no inhibitor) in each group.
- the open, solid, lighter-shaded, and darker-shaded bars represent control, SN50, LY, and PD, respectively.
- Figure 4f is the digital image of a western blot of signaling activation analysis of NFKB pathway activation. Bars indicate mean +/- s.e.m. n > 6 for each condition. P values are as indicated. Activation is detected between 0 and 0.5 nM for NFKB, reaching a plateau level at 5 nM.
- Figure 4g is the digital image of a western blot of signaling activation analysis of AKT pathway activation. Bars indicate mean +/- s.e.m. n > 6 for each condition. P values are as indicated. Activation is detected between 0.5 and 1 nM for AKT, reaching a plateau level at 5 nM.
- Figure 4h is the digital image of a western blot indicating AKT activation by growth factors and compounds in pj ⁇ TM ' cells, n > 9 for each condition. There are no significant differences between culture medium alone and NGF or
- Figure 5a is a bar graph disclosing that Compounds (iii-v) do not promote death of mature oligondendrocytes and inhibits proNGF-induced death.
- Mature oligondendrocytes were treated as indicated and cell death assessed by determining the proportion of MBP-positive cells that are also TUNEL-positive. hi the absence of pro-NGF, compounds did not promote cell death. In the presence of
- Figure 5b is a line graph showing proNGF displacement from p75 NTR by
- Figure 6 demonstrates that Compound (iii) blocks A ⁇ -induced neural degeneration.
- Figure 6a is a bar graph representing percentage of surviving hippocampal neuronal cells after addition of A ⁇ 1-42 (10 ⁇ M or 30 ⁇ M). Addition of APM 2 resulted in an approximate 40% loss of neurons after 3 days of exposure. Addition of NGF (100 pg/ml) did not protect against Ap 1-42 .
- Figure 6b is a bar graph representing the percentage of surviving hippocampal neural cells after addition of A ⁇ 1-42 (10 ⁇ M) with test compounds.
- disorders related to degeneration or dysfunction of cells expressing p75 such as neurodegenerative disorders, alterations in neurotrophin localization, expression levels of neurotrophins, expression levels of the receptors that bind neurotrophins, and/or receptor signaling and functional outcomes can occur.
- alterations in signaling pathways or other mechanisms that are linked to p75 receptor mechanisms and that can be regulated by p75 signaling can occur.
- Other disorders involve cells not expressing the p75 receptor however, cells expressing p75 have the ability to compensate for impairment or loss of non p75-expressing cells.
- the methods and compounds of the present application relate to compounds having binding specificity for a p75 NTR molecule.
- Compounds having binding specificity for p75 NTR are suitable for positively regulating survival and/or inhibiting degeneration of neural and other cells, e.g. inhibition or reversal of neuronal spine loss.
- the compounds promote survival signaling and/or inhibit degenerative or dysfunctional signaling, hi cells susceptible to neurotrophin-induced death, the compounds do not induce apoptosis, but inhibit neurotrophin-mediated death.
- a disorder involving degeneration or dysfunction of cells expressing p75 includes, but is not limited to disorders related to upregulation of p75. Such disorders include neurodegenerative disorders, as well as conditions involving degeneration of p75 NTR -expressing cells, such as hair loss.
- the p75 receptor is expressed by various cell types including neurons, oligodendrocytes, astrocytes and microglia.
- Compounds targeting p75 receptors expressed by neurons can be used to prevent loss of function, degeneration and/or death of neurons in a number of nervous system disorders including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neuropathies, myopathies and various forms of retinal degeneration, hi each of these disorders, neurons and other cells expressing p75 are affected.
- nervous system disorders including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neuropathies, myopathies and various forms of retinal degeneration, hi each of these disorders, neurons and other cells expressing p75 are affected.
- Compounds targeting p75 receptors expressed by oligodendrocytes can be used to prevent loss of function, degeneration and/or death of oligodendrocytes in a number of nervous system disorders including, but not limited to, multiple sclerosis, spinal cord injury and perinatal anoxia.
- Compound targeting p75 receptors expressed by microglia can be used to inhibit deleterious activation of microglia and thereby decrease the inflammatory component of neurodegenerative and other disorders.
- p75 receptor a number of cell populations express the p75 receptor. These include hair follicle cells, hepatic cells, vascular endothelial, vascular smooth muscle cells, cardiomyocytes. In addition, the p75 receptor is expressed by certain tumor cells such as those involved in breast or prostate cancer.
- compounds targeting p75 receptors can be used for the following indications: to prevent loss of hair follicle cells and thereby prevent hair loss; to prevent hepatic cirrhosis and promote liver regeneration; to regulate angiogenesis and promote neovascularization in the setting of diabetic wounds or other ischemic settings; to prevent cardiomyopathy by preventing myocardial cell loss or by stimulating growth of new cardiomyocytes either in the setting of ischemia or after myocardial infarction; and to inhibit tumor cell growth.
- p75 is expressed by stem cells and is known to regulate stem cell growth; therefore, p75 ligands can be used to promote stem cell growth as part of a strategy to promote tissue and organ regeneration.
- P75 receptor ligands can also be used to tag or identify cells expressing p75 or having upregulated p75 as part of diagnostic or cell- harvesting strategy.
- neurodegenerative disorder includes any disorder characterized by neural damage or dysfunction and includes but is not limited to Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, and peripheral nerve injury.
- the compounds disclosed herein function as ligands at the p75 neurotrophin receptor and thereby induce intracellular signaling that prevents cellular degeneration or death and/or upregulates cell function or growth.
- the intracellular signaling mechanisms regulated by the p75 receptor are fundamental mechanisms present in essentially all cell types; therefore, it is expected that any cell or tissue expressing this receptor would be amendable to treatment with these compounds for the goal of preventing cellular or tissue degeneration, promoting cell survival and/or for upregulating function or growth.
- alkyl refers to an optionally substituted straight-chain or branched-chain alkyl radical having from 1 to about 20 carbon atoms.
- the term also includes optionally substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms.
- alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
- Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
- Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C 1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- Higher alkyl refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, hi certain embodiments, "alkyl” refers, in particular, to C 1-8 straight-chain alkyls.
- alkyl refers, in particular, to C 1-8 branched-chain alkyls. Alkyl groups can be optionally substituted.
- heteroalkyl refers to alkyl groups, as described above, in which one or more skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof.
- heteroalkyl also includes alkyl groups in which one 1 to about 6 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof, as well as those in which 1 to 4 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof and those in which 1 to 2 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof. Heteroalkyl groups are optionally substituted.
- alkenyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms.
- the term also includes optionally substituted straight-chain or branched-chain hydrocarbon radicals having one or more carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
- alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and the like.
- Suitable alkenyl groups include allyl.
- alkenyl and/or substituted alkenyl include allyl groups, such as but not limited to, allyl, methylallyl, di-methylallyl, and the like.
- allylic position or “allylic site” refers to the saturated carbon atom of an allylic group.
- a group such as a hydroxyl group or other substituent group, attached at an allylic site can be referred to as “allylic.”
- 1 -alkenyl refers to alkenyl groups where the double bond is between the first and second carbon atom.
- alkynyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 12 carbon atoms.
- the term also includes optionally substituted straight-chain or branched-chain hydrocarbon radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
- alkynyl radicals include ethynyl, propynyl, butynyl and the like.
- “1 -alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom.
- Cyclic alkyl and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, alternately from about 3 to about 6 carbon atoms.
- the cycloalkyl group can be optionally partially unsaturated.
- the cycloalkyl group also can be optionally substituted as defined herein.
- Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
- the cycloalkyl group can be optionally substituted with a linking group, such as an alkylene group as defined hereinabove, for example, methylene, ethylene, propylene, and the like, hi such cases, the cycloalkyl group can be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, and the like.
- a linking group such as an alkylene group as defined hereinabove, for example, methylene, ethylene, propylene, and the like
- the cycloalkyl group can be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, and the like.
- multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradaniantyl.
- heterocyclic alkyl and “heterocycloalkyl” refer to cyclic groups of 3 to 6 atoms, or 3 to 10 atoms, containing at least one heteroatom. hi one aspect, these groups contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups may be substituted.
- aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
- aryl is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety.
- the common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine.
- the aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others, all of which can be optionally substituted.
- aryl means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.
- aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like, all optionally substituted.
- the aryl group can be optionally substituted (a "substituted aryl") with one or more aryl group substituents, which can be the same or different, wherein "aryl group substituent” includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and — NR 1 R", wherein R' and R" can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.
- substituted aryl includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
- aryl groups include, but axe not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.
- R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
- the presence or absence of the R group and number of R groups is determined by the value of the integer n.
- Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group.
- n is one (1) comprises compound groups including: wherein the one (1) R substituent can be attached at any carbon on the benzofuran parent structure not occupied by another designated substituent, as in this case carbon 6 is substituted by X and carbon 2 is substituted by Y.
- a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
- Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
- Heterocyclic aryl or “heteroaryl” groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N- lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
- carrier ring refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and carbocyclic aryl rings.
- heterocyclic ring refers to a saturated or unsaturated monocyclic or bicyclic ring having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms.
- heterocycloalkyl and heterocyclic aryl rings are examples of heterocyclic aryl rings.
- the term "optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclic alkyl, hydroxyl, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl,-carboxamido, nitro, acyloxy, arninoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -
- the compounds described by the presently disclosed subject matter contain a linking group.
- linking group comprises a chemical moiety which is bonded to two or more other chemical moieties to form a stable structure.
- Representative linking groups include but are not limited to a furanyl, phenylene, thienyl, or pyrrolyl radical bonded two or more aryl groups.
- Alkylene refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
- the alkylene group can be straight, branched or cyclic.
- the alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
- An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.
- alkenylene denotes an acyclic carbon chain (i.e., having an open-chain structure) having a carbon-to-carbon double bond and is represented by the formula C n H 2n-2 , which optionally can be substituted one or more times.
- alkenylene groups include, but are not limited to, ethenylene, propenylene, 1- or 2-butenylene, 1-, or 2-pentylene, and the like.
- acyl refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent (i.e., as represented by RCO-, wherein R is an alkyl or an aryl group as defined herein).
- RCO- substituent
- acyl specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.
- alkoxyl or "alkoxyalkyl” refer to an alkyl-O-- group wherein alkyl is as previously described.
- alkoxyl as used herein can refer to C 1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t- butoxyl, and pentoxyl.
- Aryloxyl refers to an aryl-O-- group wherein the aryl group is as previously described, including a substituted aryl.
- aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
- Aralkyl refers to an aryl-alkyl- group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl.
- exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
- Aralkyloxyl refers to an aralkyl-O— group wherein the aralkyl group is as previously described.
- An exemplary aralkyloxyl group is benzyloxyl.
- Dialkylamino refers to an -NRR' group wherein each of R and R' is independently an alkyl group and/or a substituted alkyl group as previously described.
- exemplary alkylamino groups include ethylmethylamino, dimethylamino, and diethylamino.
- Alkoxycarbonyl refers to an alkyl-O— CO-- group.
- exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.
- Aryloxycarbonyl refers to an aryl-O ⁇ CO ⁇ group.
- exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
- Alkoxycarbonyl refers to an aralkyl-O ⁇ CO— group.
- An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
- Carbamoyl refers to an H 2 N-CO-- group.
- Alkylcarbamoyl refers to a R 1 RN-CO-- group wherein one of R and R 1 is hydrogen and the other of R and R is alkyl and/or substituted alkyl as previously described.
- Dialkylcarbamoyl refers to a RRN-CO-- group wherein each of R and
- R' is independently alkyl and/or substituted alkyl as previously described.
- acyloxyl refers to an acyl-O— group wherein acyl is as previously described.
- Acylamino refers to an acyl-NH— group wherein acyl is as previously described.
- Aroylamino refers to an aroyl-NH— group wherein aroyl is as previously described.
- amino refers to the -NH 2 group.
- cyano refers to the -CN group.
- halo refers to fluoro, chloro, bromo, and iodo groups.
- hydroxyl refers to the -OH group.
- hydroxyalkyl refers to an alkyl group substituted with an —
- mercapto refers to the -SH group.
- nitro refers to the -NO 2 group.
- thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
- cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing one or more rings, for example, one ring, two rings, three rings, or four rings, with three or more carbon atoms per ring, for example, 3, 4, 5, 6, 7, or 8 carbon atoms per ring.
- exemplary cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
- Cycloalkenyl groups can be optionally substituted, such as with one or more substituents, e.g. 1, 2, 3, or 4 substituents, at any available point of attachment.
- substituents include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
- substituted cycloalkenyl refers to a cycloalkenyl group substituted with one or more substituents, preferably 1, 2, 3, or 4 substituents, at any available point of attachment.
- substituents include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
- R groups such as groups R 1 and R 2 , or groups X and Y
- R groups can be identical or different.
- R 1 and R 2 can be substituted alkyls, or R 1 can be hydrogen and R can be a substituted alkyl, and the like.
- a named "R”, “R',” “X,” “Y,” “Y'”, “A,” “A”', “B,” “L,” or “Z” group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein.
- certain representative "R,” “X,” and “Y” groups as set forth above are defined below. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.
- treatment covers any treatment of a disease and/or condition in an animal or mammal, particularly a human, and includes: (i) preventing a disease, disorder and/or condition and/or symptoms from occurring in a person which can be predisposed to the disease, disorder and/or condition, or at risk for being exposed to an agent that can cause the disease, disorder, and/or condition and/or symptoms; but, has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder and/or condition, and/or symptoms i.e., arresting its development; and (iii) relieving the disease, disorder and/or condition, and/or symptoms i.e., causing regression of the disease, disorder and/or condition, iv) the augmentation of compensatory mechanisms, such as promotion of stem cells, that while not treating the primary disease can lead to reduced symptoms and improved function.
- mimetic refers to a compound having similar functional and/or structural properties to another known compound or a particular fragment of that known compound, such as a known compound of biological origin, e.g., a polypeptide or fragment thereof.
- Binding specificity refers to the ability of a protein or other type of molecule capable of recognizing and interacting with a complementary site on another protein or other type of molecule.
- pharmacophore refers to a specific model or representation of a molecular moiety capable of exerting a selected biochemical effect, e.g., inhibition of an enzyme, binding to a receptor, chelation of an ion, and the like.
- a selected pharmacophore can have more than one biochemical effect, e.g., can be an inhibitor of one enzyme and an agonist of a second enzyme.
- a therapeutic agent can include one or more pharmacophores, which can have the same or different biochemical activities.
- derivative refers to a compound chemically modified so as to differentiate it from a parent compound. Such chemical modifications can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group.
- a derivative compound can be modified by, for example, glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the compound from which it was derived.
- hydrophilicity is used in the common manner of the field as having an affinity for water; readily absorbing and/or dissolving in water.
- lipophilicity is used in the common manner of the field as having an affinity for, tending to combine with, or capable of dissolving in lipids.
- amphipathicity describes a structure having discrete hydrophobic and hydrophilic regions. Thus, one portion of the structure interacts favorably with aqueous and other polar media, while another portion of the structure interacts favorably with non-polar media.
- solubility describes the maximum amount of solute that will dissolve in a given amount of solvent at a specified temperature.
- bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of compound administered to a subject. The term further encompasses the rate and extent of absorption of compound that reaches the site of action.
- solvate means a complex formed by solvation (the combination of solvent molecules with molecules or ions of the active agent of the present invention), or an aggregate that consists of a solute ion or molecule (the active agent of the present invention) with one or more solvent molecules.
- hydrate include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc.
- the pharmaceutically acceptable salt of the present compound may also exist in a solvate form.
- the solvate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention.
- Solvates including hydrates, may be found in stoichiometric ratios, for example, with two, three, four salt molecules per solvate or per hydrate molecule.
- Solvents used for crystallization such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, e.g. ethyl acetate; may be embedded in the crystal grating.
- prodrug refers to any compound that when administered to a biological system generates the drug substance (a biologically active compound) in or more steps involving spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), or both.
- Standard prodrugs are formed using groups attached to functionality, e.g. HO-, HS--, HOOC-, R 2 N-, associated with the drug substance that cleave in vivo. Prodrugs for these groups are well known in the art and are often used to enhance oral bioavailability or other properties beneficial to the formulation, delivery, or activity of the drug.
- Standard prodrugs include, but are not limited to, carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
- the compounds of the present invention may accordingly exist as enantiomers. Where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such stereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. Where the compounds possess geometrical isomers, all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
- Tautomers of the compounds of the invention are encompassed by the present application.
- a carbonyl includes its hydroxyl tautomer.
- the present application discloses a compound having binding specificity for a p75 NTR molecule.
- the compound having binding specificity for a p75 NTR molecule is a mimetic of a neurotrophin ⁇ -turn loop.
- the compound comprises a pharmacophore substantially identical to the pharmacophore illustrated in Figure Ic.
- the compound is a small molecule or a peptide.
- the present application discloses a compound selected from the group consisting of:
- a compound is selected from the group consisting of a compound of Formula A or Formula B:
- n is an integer from 0 to 8.
- L 1 and L 2 are a linking group selected from the group consisting of alkylene, substituted alkylene, cycloalkyl, substituted cycloalkyl, cycloalkene, substituted cycloalkene, aryl, substituted aryl, alkenylene, and substituted alkenylene;
- R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, cyano, nitro, mercapto, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- a 1 , A 2 , A 3 , A 4 , and A 5 are each independently selected from the group consisting of N and CH;
- B 1 , B 2 , B 3 , B 4 , and B 5 are each independently selected from the group consisting of O, S, and NR 4 , wherein R 4 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl; and
- D 1 and D 2 are selected from the group consisting of:
- each R 5 , R 6 , R 8 , R 9 , and R 10 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; each R 7 is independently selected from the group consisting of H, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, acyloxyl, and alkoxyl; or
- R 7 and R 5 or R 7 and R 9 together represent a C 2 to C 10 alkyl, C 2 to Ci 0 hydroxyalkyl, or C 2 to C 10 alkene; or a pharmaceutically acceptable salt thereof.
- L 1 and L 2 are each independently -(CH 2 ) m -, wherein m is an integer from 1 to 8.
- the compound of Formula (A) has the following structure:
- m is an integer from 1 to 8.
- R 1 and R 2 are each independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- R 5 and R 6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, allcylaminoaUcyl, and alkoxycarbonyl.
- the compound of Formula (A) has the following structure: Compound (iii).
- the compound of Formula (B) has the following structure:
- m is an integer from 1 to 8.
- R 3 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, halo, hydroxyl, alkoxyl, aryl, aryloxyl, substituted aryl, and aralkyloxyl;
- R 5 and R 6 are each independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl.
- the compound of Formula (B) has the following structure:
- the compound of Formula (A) is not: Compound (Hi); and the compound of Formula (B) is not:
- the neurotrophin is a nerve growth factor (NGF).
- the ⁇ -turn loop is loop 1 of the NGF.
- the compound has the formula:
- the compound has binding specificity for a neurotrophin binding site of the p75 NTR molecule.
- the compound comprises a derivative of a parent compound having binding specificity for a p75 NTR molecule, wherein the derivative also has binding specificity for the p75 NTR molecule.
- the derivative exhibits an enhancement in at least one of the characteristics selected from the group consisting of hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
- R 5 is morpholinyl, thiomorpholinyl, tetrahydro-2H-pyran, 1-methylpiperazinyl, piperidinyl, or pyrrolidinyl; and each of R and R is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- m is 2; X is 0; R and R each is hydrogen; R is optionally substituted C 1 -C 4 alkyl; R 5 is a nitrogen-bound morpholinyl, 1-methylpiperazinyl, piperidinyl, or pyrrolidinyl; and each of R 1 and R 1 is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- the compound has the structure of Formula IA:
- each of R 1 , R 1 , R 3 , and R 4 independently is hydrogen or optionally substituted alkyl; and n is 0, 1, 2, 3, 4, or 5.
- Another aspect is the compound having the structure of Formula IA wherein each of R 1 , R 1 , R 3 , and R 4 independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; and n is 1, 2, 3, or 4.
- n is 2; each of R and R 1 is hydrogen; R 3 is methyl and R is sec-butyl.
- R 5 is a heterocycloalkyl bound via a heteroatom; m is 2; and X is 0.
- R 2 and R 2 each is hydrogen; and R 3 is optionally substituted C 1 -C 4 alkyl.
- R 5 is a nitrogen-bound morpholinyl, 1-methylpiperazinyl, piperidinyl, or pyrrolidinyl; and each of R 1 and R 1 is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- the compound has the structure of Formula IB:
- One aspect is a compound having the structure of Formula IB wherein each of R 1 , R 1 , R 3 , and R 4 independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; and n is 1, 2, 3, or 4.
- n is 2; each of R 1 and R 1 is hydrogen; R 3 is methyl and R is sec-butyl.
- R 5 is a heterocycloalkyl bound via a heteroatom; m is 2; and X is 0. hi another embodiment, R and R each is hydrogen; and R 3 is optionally substituted C 1 -C 4 alkyl.
- R 5 is a nitrogen-bound morpholinyl, 1-methylpiperazinyl, piperidinyl, or pyrrolidinyl; and each of R 1 and R 1 is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- q is 1, 2, 3, or 4
- t is 0, 1, 2, or 3
- the compound has the structure of Formula HA wherein p is 1, 2, 3, 4, or 5; q is 2 or 3; t is 0, 1, 2, or 3; each of Y, V, and W is independently O or S; each of R 10 and R 11 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; each of R 6 is independently -NR a R , -OH, or optionally substituted alkyl; and each of R a and R b is independently hydrogen or optionally substituted alkyl.
- each of Y, V, and W is O; q is 1; each of R 10 and R 11 is independently hydrogen or C 1 -C 4 alkyl; and each of R 12 and R 13 is independently C 1 -C 4 alkyl.
- each of R 10 and R 11 is independently hydrogen; each of R 12 and R 13 is independently -Me; and each of R 6 , R 6' , R 7 , R 7' , R 8 , R 8' , R 9 , and R 9' is independently hydrogen, -NR a R b , -OH, or optionally substituted alkyl.
- each of R 10 and R 11 is independently -H; each of R 12 and R 13 is independently -Me; q is 2; and each of R 6 , R 6' , R 7 , R 7' , R 8 , R 8' , R 9 , and R 9 is independently hydrogen, -NR a R b , -OH, or optionally substituted alkyl.
- each of R , R , R , R 7' , R 8 , R 8' , and R 9 is hydrogen; and R 9' is -N(CH 3 ) 2 .
- the compound has the structure of Formula HB:
- the compound has the structure of Formula HB wherein p is 1, 2, 3, 4, or 5; each of Y, V, and W is independently O or S; each of R 10 and R 11 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; R and R taken together with the nitrogen to which they are attached form a an optionally substituted pyridyl, an optionally substituted pyrrolyl, an optionally substituted pyrimidyl or an optionally substituted pyrazinyl.
- each of Y, V, and W is O; each of R 10 and R 11 is independently hydrogen or C 1 -C 4 alkyl; and each of R 12 and R 13 is independently C 1 -C 4 alkyl.
- each of R 10 and R 1 is independently hydrogen; each of R 12 and R 13 is independently -Me.
- each of R 10 and R 11 is independently -H; each of R 12 and R 13 is independently -Me; q is 2; and R and R " taken together with the nitrogen to which they are attached form an optionally substituted pyrrolyl.
- the compound has the structural formula
- R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl.
- the compound of Formula III is not 2-amino-3-methyl-N-(2- mo ⁇ holinoethyl)-butanamide.
- X is O; s is 0; R 22 is hydrogen; and R 22 is optionally substituted Cj-C 6 alkyl.
- R 20 and R 21 taken together with the atoms to which they are attached form an optionally substituted cycloalkyl; or R and R taken together with the atoms to which they are attached form an optionally substituted aryl.
- the compound has the structural formula
- s is 2; X is O; R 19 and R 20 taken together with the atoms to which they are attached form an optionally substituted cycloalkyl; or R 19 and R 20 taken together with the atoms to which they are attached form an optionally substituted aryl.
- the compound has the structural formula:
- the compound has a structural formula selected from the group consisting of:
- the compound has a structural formula selected from the group consisting of:
- each of Y, V, and W is independently CH 2 , NH, O or S; each of R 30 , R 31 , R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently absent, hydrogen or optionally substituted alkyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic ring; E is -CHR c R d , -NR c R d , -OR C , and -SR C ; and each of R c and R d is independently hydrogen or optionally substituted alkyl; or R c and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring or R c and R taken together with the carbon atom to which they
- the compound of Formula IV is not N-(3- (diethylamino)propyl)-2-(4,6-dimethyl-5,7-dioxo-4,5,6,7-tetraliydro-lH- benzo[d]imidazol-l-yl)acetamide.
- p is 1, 2, or 3; each of Y, V, and W is O or S; each of R 30 and R 31 is independently optionally substituted C 1 -C 4 alkyl; each of R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently hydrogen or optionally substituted C 1 -C 4 alkyl; and E is -OR C , -SR C , or -NR c R d wherein R c and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl.
- the compound has the structure of Formula IV wherein p is 1, 2, 3, or 4; each of Y, V, and W is independently O or S; each of R 30 , R 31 , R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently absent, hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or R and R taken together with the atoms to which they are attached form an optionally substituted carbocyclic ring; E is -CHR c R d , -NR c R d , -OR C , or -SR C ; and each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or R c and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring
- p is 1, 2, or 3; each of Y, V, and W is O or S; E is -OR C or -SR C ; each of R 32 , R 32' R 33 , R 34' , R 35 , R 35' , and R 36' is independently hydrogen; and each of R 30 and R 31 is independently optionally substituted C 1 -C 4 alkyl.
- p is 1, 2, or 3; each of Y, V, and W is O or S; E is NR c R d and R c and R taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl; each of R and R is independently optionally substituted C 1 -C 4 alkyl; and each of R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36 is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- p is 1; each of Y, V, and W is O; each of R 30 a healthcaren_d j purchase R31 is independently -CH 3 ; R 33 is hydrogen; and each of R 32 , R 32' R 34 , R 34' , R 35 , R 35' , R 36 , and R 36 is independently hydrogen or C 1 -C 4 alkyl.
- E is -NR 0 R and each of R c and R is independently hydrogen or optionally substituted alkyl.
- R 3 and R 3 taken together with the atoms to which they are attached form an optionally substituted cycloalkyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic aryl.
- the atoms to which they are attached form an optionally substituted cycloalkyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic aryl.
- E is -NR°R d and R° and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl.
- the compound has a structural formula selected from the group consisting of:
- the compound has a structural formula selected from the
- such compounds include:
- the present application provides a compound of
- R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36 is independently absent, hydrogen or optionally substituted alkyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic ring;
- E is -CHR c R d , -NR c R d , -OR C , and -SR 0 ; and each of R c and R d is independently hydrogen or optionally substituted alkyl; or R c and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring or R° and R d taken together with the carbon atom to which they are attached form an optionally substituted carbocyclic ring.
- the compound has the structure of Formula IVA wherein p is 1, 2, 3, or 4; V is O or S; each of R 32 , R 32' R 33 , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently absent, hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic ring; E is -CHR c R d , -NR c R d , -OR C , or -SR C ; and each of R c and R d is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; or R c and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring or R° and R taken together with the carbon atom to which
- p is 1, 2, or 3; V is O or S; E is -OR C or -SR 0 ; each of R 32 , R 32' R 33 , R 34' , R 35 , R 35' , and R 36 is independently hydrogen.
- p is 1, 2, or 3; V is O or S; E is NR°R d and R° and R d taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl; and each of R 32 , R 32 R , R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently hydrogen or optionally substituted C 1 -C 4 alkyl.
- p is 1; V is O; R 33 is hydrogen; and each of R 32 , R 32' R 34 , R 34' , R 35 , R 35' , R 36 , and R 36' is independently hydrogen or Ci-C 4 alkyl.
- E is -NR°R d and each of R° and R d is independently hydrogen or optionally substituted alkyl.
- R 34 and R 3 ⁇ taken together with the atoms to which they are attached form an optionally substituted cycloalkyl; or R 34 and R 36 taken together with the atoms to which they are attached form an optionally substituted carbocyclic aryl.
- the compound has the structural formula
- compounds disclosed herein can also be linked to molecular markers that can be detected by imaging or other modalities.
- conjugates can be prepared according to synthetic methods known to those of skill in the art and applied in diagnostic strategies designed to detect such pathological states.
- the present invention provides a compound selected from the group consisting of (2R,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide; (2R,3 S)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
- the compound is in a purity of about 80% or more. In another embodiment, the compound is in a purity of about 85% or more.
- the compound is in a purity of about 90% or more. In another embodiment, the compound is in a purity of about 95% or more. In another embodiment, the compound is in a purity of about 96% or more. In another embodiment, the compound is in a purity of about 97% or more. In another embodiment, the compound is in a purity of about 98% or more. In another embodiment, the compound is in a purity of about 99% or more. In another embodiment, the compound is in a purity of about 99.5% or more.
- the present invention provides a mixture of two or more compounds selected from the group consisting of (2S,3S)-2-amino-3-methyl- N-(2-morpholinoethyl)-pentanamide; (2R,3R)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide; (2R,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, with the proviso that when the mixture consists of (2S,3S)-2-ammo-3-methyl-N-(2- mo ⁇ holinoethyl)-pentanamide and (2R,3R)-2-amino-3-methyl-N-(2- mo ⁇ holinoeth
- the mixture consists of any two of the aforementioned four compounds. In another embodiment, the mixture consists of any three of the aforementioned four compounds. In another embodiment, the mixture consists of the aforementioned four compounds.
- the individual compounds in the mixture can be in any ratio or weight percentage. In one embodiment, any of the two or more compounds in the mixture is in an amount of about 0.5% by weight or more. In another embodiment, any of the two or more compounds in the mixture is in an amount of about 5% by weight or more. In another embodiment, each of the two or more compounds in the mixture is in an approximately equal amount.
- Scheme A provides the chemical structures of the above-mentioned compounds.
- the present invention provides a mixture of (2R,3R)- 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide and (2S,3S)-2-amino-3- methyl-N-(2-moipholinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, with the proviso that (2S,3S)-2-amino-3-methyl- N-(2-mo ⁇ holinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, is in an amount not less than about 5% by weight based on the total amount of the mixture.
- the individual compounds in the mixture can be in any ratio or weight percentage.
- the mixture consists of (2R,3R)-2-amino-3-methyl-N-(2- morpholmoethyl)-pentanamide and (2S,3S)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, in an approximately equal amount.
- the present invention provides a mixture of (2R,3S)- 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide and (2S,3R)-2-amino-3- methyl-N-(2-mo ⁇ holinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
- the individual compounds in the mixture can be in any ratio or weight percentage.
- the mixture consists of (2R,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide and (2S,3R)-2- amino-3-methyl-N-(2-m ⁇ holinoethyl)-pentanamide 5 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound selected from the group consisting of (2R,3R)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; (2R,3S)-2-amino- 3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N- (2-mo ⁇ holinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and a pharmaceutically acceptable carrier.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a mixture of two or more compounds selected from the group consisting of (2S,3S)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; (2R,3R)-2-amino-3 -methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; (2R,3 S)-2-amino- 3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N- (2-mo ⁇ holinoethyl)-pentanamide; or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and a pharmaceutically acceptable carrier, with the proviso that when the mixture consists of (2S,3S)-2-amino-3-methyl-N-(2- mo ⁇ holinoethyl)-pentanamide and
- the application provides compounds having binding specificity for a p75 NTR molecule. These compounds, along with related pharmaceutical compounds and methods, are useful in the treatment and prevention of neurodegenerative and other disorders.
- One object of the presently disclosed subject matter is to provide methods of facilitating cell survival using neurotrophin mimetics.
- a representative neurotrophin can include, but is not limited to, NGF. More particularly, the neurotrophin ⁇ -turn loop having binding specificity for a p75 NTR molecule includes, but is not limited to, loop 1 of the NGF.
- representative structures of the compound or mimetic having binding specificity for a p75 NTR molecule are capable of binding to the neurotrophin-binding site of the p75 NTR molecule.
- the compounds disclosed herein can also encompass derivatives of a parent compound, which has binding specificity for a p75 NTR molecule, wherein the derivative also has binding specificity for the p75 NTR .
- the derivative can exhibit enhancement in at least one of the characteristics selected from the group consisting of hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
- the compounds disclosed herein can encompass a pharmacophore substantially identical to the pharmacophore illustrated in Figure Ic. Representative such compounds include but are not limited to compounds encompassed by Formulas (A) and (B).
- the aforementioned individual compounds or mixtures can be used for treating a wide range of conditions and diseases described herein.
- a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a compound of Formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
- a method for treating a disorder associated with p75 expression comprising administering to a patient in need of such treatment a compound of Formula I, IA, IB, II, HA, HB, III, IV or IVA or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- the disorder is associated directly with cells expressing p75; in another embodiment, the cells do not express p75, but are affected by p75 expression.
- a method for activating a p75 receptor comprising contacting a cell containing a p75 receptor with a compound of Formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- a method for the treatment of disorders involving degeneration or dysfunction of cells expressing p75 comprising administering to a patient in need of such treatment a compound of Formula I, IA, IB, II, IIA, IIB, III, IV or IVA or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- the method of treatment comprises facilitating cell survival; in another embodiment, the method of treatment comprises inhibiting degenerative p75 signaling; in yet another embodiment, the method of treatment comprises inhibiting dysfunctional p75 signaling.
- the disorder is a neurodegenerative disorder.
- the disorder is selected from the group consisting of Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, peripheral nerve injury and hair loss.
- Compounds of Formula I, IA, IB, II, HA, IIB, III, IV or IVA or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof as disclosed herein that target p75 receptors expressed by neurons are used to prevent loss of function, degeneration and/or death of neurons in a number of nervous system disorders.
- Such disorders include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neuropathies, myopathies and various forms of retinal degeneration.
- compounds of the present application are used in the treatment of Alzheimer's disease.
- Target p75 receptors expressed by oligodendrocytes are used to prevent loss of function, degeneration and/or death of oligodendrocytes in a number of nervous system disorders including, but not limited to, multiple sclerosis, spinal cord injury and perinatal anoxia, hi another embodiment, compounds of the present application are used to treat multiple sclerosis.
- p75 receptor a number of cell populations express the p75 receptor. These include hair follicle cells, hepatic cells, vascular endothelial, vascular smooth muscle cells, cardiomyocytes. In addition, the p75 receptor is expressed by certain tumor cells such as those involved in breast or prostate cancer.
- target p75 receptors are used to: prevent loss of hair follicle cells and thereby prevent hair loss; prevent hepatic cirrhosis and promote liver regeneration; regulate angiogenesis and promote neovascularization in the setting of diabetic wounds or other ischemic settings; prevent cardiomyopathy e.g. preventing myocardial cell loss or stimulating growth of new cardiomyocytes either in the setting of ischemia or after myocardial infarction; and inhibit tumor cell growth.
- p75 is expressed by stem cells and is known to regulate stem cell growth; therefore, p75 ligands are used to promote stem cell growth as part of a strategy to promote tissue and organ regeneration.
- the compound administered to a patient in need thereof is selected from the group consisting of:
- the compound administered to a patient in need thereof is selected from the group
- a method for treating a disorder associated with p75 expression comprising administering to a patient in need of such treatment a stereoisomer of 2 amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide, including (2R,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3 S)- 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; and (2S,3R)-2-amino-3- methyl-N-(2-morpholinoethyl)-pentanamide or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- the disorder is associated directly with cells expressing p75; in another embodiment, the cells do not express p75, but are affected by p75 expression.
- a method for activating a p75 receptor comprising contacting a cell containing a p75 receptor with a stereoisomer of 2 amino-3-methyl-N-(2-mo ⁇ holinoethyl)- pentanamide, including (2R,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide; (2R,3S)-2-arnino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- a method for the treatment of disorders involving degeneration or dysfunction of cells expressing p75 comprising administering to a patient in need of such treatment a stereoisomer of 2 amino-3- methyl-N-(2-mo ⁇ holinoethyl)-pentanamide, including (2R,3R)-2-amino-3-methyl- N-(2-morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- the method of treatment comprises facilitating cell survival; in another embodiment, the method of treatment comprises inhibiting degenerative p75 signalling; in yet another embodiment, the method of treatment comprises inhibiting dysfunctional p75 signaling.
- the disorder is a neurodegenerative disorder. In another embodiment, the disorder is selected from the group consisting of Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, peripheral nerve injury and hair loss.
- Such disorders include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neuropathies, myopathies and various forms of retinal degeneration.
- compounds of the present application are used in the treatment of Alzheimer's disease.
- Stereoisomers of 2 amino-3-methyl-N-(2- morpholinoethyl)-pentanamide including (2R,3R)-2 ⁇ amino-3-methyl-N-(2- morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3 ⁇ methyl-N-(2-morpholinoethyl)- pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof as disclosed herein that target p75 receptors expressed by oligodendrocytes are used to prevent loss of function, degeneration and/or death of oligodendrocytes in a number of nervous system disorders including, but not limited to, multiple sclerosis, spinal cord injury and perinatal anoxia.
- compounds of the present application are used to treat multiple sclerosis.
- a number of cell populations express the p75 receptor. These include hair follicle cells, hepatic cells, vascular endothelial, vascular smooth muscle cells, cardiomyocytes.
- the p75 receptor is expressed by certain tumor cells such as those involved in breast or prostate cancer.
- stereoisomers of 2 amino-3-methyl-N-(2- morpholinoethyl)-pentanamide including (2R,3R)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide; (2R,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide; and (2S,3R)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof as disclosed herein that target p75 receptors are used to: prevent loss of hair follicle cells and thereby prevent hair loss; prevent hepatic cirrhosis and promote liver regeneration; regulate angiogenesis and promote neovascularization in the setting of diabetic wounds or other ischemic settings; prevent cardiomyopathy e.g.
- p75 is expressed by stem cells and is known to regulate stem cell growth; therefore, p75 ligands are used to promote stem cell growth as part of a strategy to promote tissue and organ regeneration.
- the method comprises administering to a patient in need of such treatment a pharmaceutical composition comprising a mixture of two or more compounds selected from the group consisting of (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3S)-2-amino- 3-methyl-N-(2-morpholinoethyl)-pentanamide; and (2S,3R)-2-amino-3-methyl-N- (2-morpholinoethyl)-pentanamide; or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, with the proviso that when the mixture consists of (2S,3S)- 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide and (2R,3R)-2
- the method comprises administering, to a patient in need of such treatment a pharmaceutical composition comprising a mixture of (2R,3S)-2-amino- 3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide and (2S,3R)-2-amino-3-methyl-N-(2 ⁇ morpholinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
- a pharmaceutical composition comprising a mixture of (2R,3S)-2-amino- 3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide and (2S,3R)-2-amino-3-methyl-N-(2 ⁇ morpholinoethyl)-pentanamide, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
- the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
- Intraarterial and intravenous injection as used herein includes administration through catheters.
- the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
- the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- a suitable vehicle e.g., sterile pyrogen-free water
- suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
- formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
- biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
- Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
- compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
- a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane- diol or prepared as a lyophilized powder.
- Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
- a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
- the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
- an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
- Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
- the compounds can further be formulated for topical administration.
- Suitable topical formulations include one or more compounds in the form of a liquid, lotion, cream or gel. Topical administration can be accomplished by application directly on the treatment area. For example, such application can be accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by spray application of a liquid formulation onto the treatment area.
- bioimplant materials can be coated with the compounds so as to improve interaction between cells and the implant.
- Formulations of the compounds can contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the formulations comprising the compound can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
- the compounds can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- compositions containing the active ingredient may be in any form suitable for the intended method of administration.
- tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
- Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharine, cellulose, magnesium carbonate, etc. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
- excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax maybe employed.
- inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
- granulating and disintegrating agents such as maize starch, or alginic acid
- binding agents such as starch, gelatin
- Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example calcium phosphate or kaolin
- soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
- a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum trag
- the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
- Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
- These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- the pharmaceutical formulations comprising the compounds of the present application can include an agent which controls release of the compound, thereby providing a timed or sustained release compound.
- Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
- non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
- Oral carriers can be elixirs, syrups, capsules, tablets and the like.
- Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsif ⁇ ers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols
- the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
- the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
- Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
- a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents; it can also be an encapsulating material.
- the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
- the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active compound.
- suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
- Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
- Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
- Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
- the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. Salts
- the disclosed compounds can further comprise pharmaceutically acceptable salts.
- Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphate
- Base addition salts include but are not limited to, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammom ' um, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like.
- Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
- Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
- Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
- the present application provides treatment of disorders associated with p75 expression.
- the present application provides treatment of disorders involving degradation or dysfunction of cells expressing p75.
- a method for activating p75 receptors comprising contacting a cell containing a p75 receptor with one or more compounds of the present application or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.
- nervous system disorders including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, spinal cord injury, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, neuropathies, myopathies and various forms of retinal degeneration, based on the ability of the compounds of the present application to target p75 receptors expressed by neurons or other cells.
- a nervous system disorders including, but not limited to, multiple sclerosis, spinal cord injury and perinatal anoxia, based on the ability of the compounds of the present application to target p75 receptors expressed by oligodendrocytes, microglia or astrocytes.
- methods for treating diseases other than those of the nervous system including methods to: prevent loss of hair follicle cells and thereby prevent hair loss; prevent hepatic cirrhosis and promote liver regeneration; regulate angiogenesis and promote neovascularization in the setting of diabetic wounds or other ischemic settings; prevent cardiomyopathy e.g.
- p75 is expressed by stem cells and is known to regulate stem cell growth; therefore, p75 ligands disclosed herein can be used to promote stem cell growth as part of a strategy to promote tissue and organ regeneration.
- the present application also provides methods of treating neurodegenerative and other disorders or conditions in a subject.
- the methods of the present application involve administration of a compound having binding specificity for a p75 NTR molecule in a subject to treat a neurodegenerative disorder or other disorder or condition.
- the compound can be administered in an amount effective to induce survival signaling and/or inhibit proNGF-induced cell death, which has been determined to be associated with neurodegenerative and other disorders.
- the condition to be treated can be any condition which is mediated, at least in part, by binding of neurotrophins to p75 NTR .
- Such conditions include, but are not limited to, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation, multiple sclerosis, peripheral nerve injury, and hair loss.
- the condition to be treated can be any condition which is mediated, at least in part, by aberrant signaling of the p75 receptor, hi one embodiment, the aberrant signaling is mediated by the presence or absence of neurotrophm binding; in another embodiment the aberrant signaling is not mediated by the presence or absence of neurotrophm binding. In one variation aberrant signaling occurs in the absence of neurotrophin binding.
- Compounds having binding specificity for p75 TR as disclosed herein can be used to treat cell degeneration, including preventing neurodegeneration such as, for example, neurodegeneration caused by chemotherapy and/or neurodegenerative disorders, as well as other conditions such as inducing hair follicle cell survival after hair follicle cell degeneration caused by, for example, chemotherapy.
- the present application further provides for novel methods of facilitating cell survival.
- Representative cells include, but are not limited to, septal, hippocampal, cortical, sensory, sympathetic, motor neurons, hair follicle cells, progenitor, and stem cells. Generally, such cells include neurons, oligodendrocytes and hair follicle cells.
- the methods comprise treating a cell with a compound having binding specificity for a p75 NTR molecule, whereby the compound induces survival signaling and inhibits proNGF-induced cell death.
- the present application also provides for a novel method of optimizing cell function comprising use of the compounds disclosed herein. hi one embodiment, decreased cell survival is not the primary underlying disease mechanism; in another embodiment, decreased cell survival is the primary underlying disease mechanism. Administration
- the present application discloses a method of administering compounds having binding specificity for p75 TR in order to ameliorate a condition mediated by p75 NTR binding in a subject.
- the method can comprise the step of administering to a subject an effective amount of a compound having binding specificity for p75 NTR , such as any of the compounds disclosed herein.
- administering can be effected or performed using any of the various methods known to those skilled in the art.
- the compound can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermally, intramuscularly, topically, enteral (e.g., orally), rectally, nasally, buccally, sublingually, vaginally, by inhalation spray, by drug pump or via an implanted reservoir in dosage formulations containing conventional non-toxic, physiologically acceptable carriers or vehicles.
- the presently disclosed compounds can be administered to a localized area in need of treatment. This can be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, transdermal patches, by injection, by catheter, by suppository, or by implant (the implant can optionally be of a porous, non-porous, or gelatinous material), including membranes, such as sialastic membranes or fibers.
- the form in which the compound is administered (e.g., syrup, elixir, capsule, tablet, solution, foams, emulsion, gel, sol) will depend in part on the route by which it is administered.
- mucosal e.g., oral mucosa, rectal, intestinal mucosa, bronchial mucosa
- nose drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used.
- the compound can also be used to coat bioimplantable materials to enhance neurite outgrowth, neural survival, or cellular interaction with the implant surface.
- administration can comprise administering to the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods, upon a review of the instant disclosure.
- the compounds of the present application can be employed as the sole active agent in a pharmaceutical or can be used in combination (e.g., administered proximate in time to each other or even in the same formulation) with other active ingredients, e.g., neurotrophins, or other factors or drugs which can facilitate neural survival or axonal growth in neurodegenerative diseases, including but not limited to amyloid- ⁇ inhibitors, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, and N-methyl-D-aspartate subtype of glutamate receptor antagonists.
- active ingredients e.g., neurotrophins, or other factors or drugs which can facilitate neural survival or axonal growth in neurodegenerative diseases, including but not limited to amyloid- ⁇ inhibitors, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, and N-methyl-D-aspartate subtype of glutamate receptor antagonists.
- Compounds of the invention are generally administered in a dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose. Alternately the dose can be from about 0.1 mg/kg/dose to about 10 mg/kg/dose; or about 1 mg/kg/dose to 10 mg/kg/dose. In some dosages, the compounds disclosed herein are administered at about 5 mg/kg/dose. Time release preparations may be employed or the dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), compounds are administered to the affected tissue at a rate from about 0.05 to about 10 mg/kg/hour, alternately from about 0.1 to about 1 mg/kg/hour.
- topically administered formulations are administered in a dose of about 0.5 mg/kg/dose to about 10 mg/kg/dose range.
- topical formulations are administered at a dose of about 1 mg/kg/dose to about 7.5 mg/kg/dose or even about 1 mg/kg/dose to about 5 mg/kg/dose.
- a range of from about 0.1 to about 100 mg/kg is appropriate for a single dose. Continuous administration is appropriate in the range of about 0.05 to about 10 mg/kg. Topical administration is appropriate for conditions such as hair loss or wound revascularization.
- Drug doses can also be given in milligrams per square meter of body surface area rather than body weight, as this method achieves a good correlation to certain metabolic and excretionary functions.
- the compounds disclosed herein can take the form of a mimetic or fragment thereof, it is to be appreciated that the potency, and therefore dosage of an effective amount can vary. However, one skilled in the art can readily assess the potency of a compound of the type presently envisioned by the present application.
- compounds of the present application are generally administered on an ongoing basis. In certain settings administration of a compound disclosed herein can commence prior to the development of disease symptoms as part of a strategy to delay or prevent the disease. In other settings a compound disclosed herein is administered after the onset of disease symptoms as part of a strategy to slow or reverse the disease process and/or part of a strategy to improve cellular function and reduce symptoms.
- Compounds have been developed that cross the blood brain barrier and hence would be delivered by oral administration or by other peripheral routes. Compounds that do not cross the blood brain barrier are applied for targets outside of the central nervous system. For targets and tissues outside of the nervous system, compounds are applied in either acute or chronic settings by other oral or directed target administration such as by topical application.
- dosage range will depend on the particular compound, and its potency.
- the dosage range is understood to be large enough to produce the desired effect in which the neurodegenerative or other disorder and the symptoms associated therewith are ameliorated and/or survival of the cells is achieved, but not be so large as to cause unmanageable adverse side effects.
- the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
- the dosage can also be adjusted by the individual physician in the event of any complication. No unacceptable toxicological effects are expected when compounds disclosed herein are used in accordance with the present application.
- An effective amount of the compounds disclosed herein comprise amounts sufficient to produce a measurable biological response.
- Actual dosage levels of active ingredients in a therapeutic compound of the present application can be varied so as to administer an amount of the active compound that is effective to achieve the desired therapeutic response for a particular subject and/or application.
- a minimal dose is administered, and the dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art.
- a preferred subject is a vertebrate subject.
- a preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal.
- the subject treated by the presently disclosed methods is desirably a human, although it is to be understood that the principles of the present application indicate effectiveness with respect to all vertebrate species which are to included in the term "subject.”
- a vertebrate is understood to be any vertebrate species in which treatment of a neurodegenerative disorder is desirable.
- the term "subject” includes both human and animal subjects.
- veterinary therapeutic uses are provided in accordance with the present application.
- the present application provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos.
- mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos.
- animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses.
- domesticated fowl i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economical importance to humans.
- livestock including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like.
- a “protected” compound or derivatives means derivatives of a compound where one or more reactive site or sites or functional groups are blocked with protecting groups.
- Protected derivatives are useful in the preparation of the compounds of the present invention or in themselves; the protected derivatives may be the biologically active agent.
- An example of a comprehensive text listing suitable protecting groups may be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
- the protection group for the amino acid is a Boc group.
- the coupling agent can be HATU, HBTU, EDC/HOBt, or DCC/DMAP.
- the deprotection reagent can be 4 M HCl in MeOH, 4M HCl in water, or TFA in DCM.
- an amine or aniline is coupled with an N-protected amino acid and this coupled intermediate is deprotected to give a final compound or another intermediate.
- the second intermediate can be further modified or directly go through this coupling-deprotection cycle one more time to give the final compound.
- A6a was dissolved in THF.
- BH 3 -THF was added slowly to the above solution. Bubbles were observed and the reaction mixture was stirred over night at RT.
- LC-MS showed the completion of the reaction. THF was then removed under vacuum and the aqueous solution was extracted with AcOEt. AcOEt was dried over Na 2 SO 4 and removed. The residue was dissolved in methanol and subjected to prep-HPLC separation. After removal of the solvent, the product formic acid salt was converted to HCl salt by co-evaporating with 50 mL 1.25 HCl methanol solution three times (91 mg). Compound 12 was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 14 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-Leu-OH.
- Compound 14 (175mg) was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 15 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-Leu-OH.
- Compound 14 (175mg) was characterized by 1 H NMR, LC-MS
- Compound 15 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-D-t-butylglycine- OH.
- Compound 15 120mg was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 16 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-Asp(OTBU)-OH.
- Compound 16 (50mg) was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 17 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-Glu(OTBU)-OH.
- Compound 17 (60mg) was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 17 was prepared according to the method of preparation of Compound 13, except that Boc-Phe-OH was replaced with Boc-Pro-OH.
- Compound 18 (80mg) was characterized by 1 H NMR, LC-MS and HPLC.
- 1 H NMR (D 2 O), ⁇ : 4.27 (t, J 7.38 Hz, IH), 3.91-4.10 (m, 2H), 3.60-3.81 (m, 3H), 3.37-3.57 (m, 3H), 3.19-3.37 (m, 4H), 3.04-3.19 (m, 2H), 2.25-2.40 (m, IH), 1.85-2.02 (m, 3H).
- Example 19 Preparation of Compound 19
- the coupling agent can be HATU or HBTU.
- the acid used to remove a protection group such as Boc can be 4 M HCl in MeOH or 4M HCl in water.
- A26a was dissolved in aqueous HCOH and NaCNBH 3 was added. The reaction mixture was stirred for 2 hours at RT.
- Compound 27 (180mg) was prepared by the same method as Compound 26 using an appropriate starting material in place of 1,2-cyclohexane diamine. The only difference was that the reaction was carried out at 130 0 C for 6 hours, and the final formic acid salt was converted to HCl salt by co evaporating with 50 mL of 1.25N HCl methanol solution three times. Compound 27 was characterized by 1 H NMR, LC-MS and HPLC.
- Compound 28 (130 mg) was prepared by the same method as Compound 27 using a derivatized amine in place of 1,2-cyclohexane diamine, and the final formic acid salt was converted to HCl salt by co evaporating with 50 mL 1.25N HCl methanol solution three times.
- Compound 28 was characterized by 1 H NMR, LC- MS and HPLC.
- 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by a method shown in Scheme 4 below.
- 2-aminoethanol (Compound IE) is transformed to its derivative with a leaving group (Compound 2E).
- the leaving group include halides and alkoxy or other activated hydroxyl group.
- Compound 2E reacts with morpholine at a neutral or basic condition to yield 2-morpholinoethanamine (Compound 3E).
- the aforementioned two steps may also be performed continuously as one step with Compound 2E being generated in situ.
- Compound 3 E can be prepared from Compound IE directly through a Mitsunobu reaction wherein the hydroxyl group of Compound IE is activated by diethyl azodicarboxylate (DEAD) before morpholine is added.
- DEAD diethyl azodicarboxylate
- the final product, 2-amino-3-methyl-N-(2-moipholinoethyl)-pentanamide (Compound 5E) can be obtained by coupling 2-morpholinoethanamine with 2-amino-3- methylpentanoic acid (Compound 4E) via a peptide coupling agent.
- peptide coupling agent examples include l,r-carbonyldiimidazole (CDI), hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1- hydroxybenzo-7-azatriazole (HOAt), and the like.
- a chiral 2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide (Compound 5E) can be obtained by using the corresponding chiral 2-amino-3- methylpentanoic acid (Compound 4E) in the above coupling step.
- (2S,3S)-2-amino-3-methyl-N-(2-mo ⁇ holinoethyl)-pentanamide; (2R,3R)-2-amino- 3 -methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3 -methyl-N-(2- mo ⁇ holinoethyl)-pentanamide; and (2S,3R)-2-ammo-3-methyl-N-(2- morpholinoethyl)-pentanamide can be obtained by using (2S,3S)-2-amino-3- methylpentanoic acid, i.e., L-isoleucine; (2R,3R)-2-amino-3-methylpentanoic acid, i.e., D-isoleucine; (2R,3S)-2-amino-3-methylpentanoic acid, i.e., D-alloisoleucine; and
- the chiral purity, also known as, enantiomeric excess or EE, of a chiral Compound 5E can be determined by any method known to one skilled in the art.
- a chiral Compound 5E can be hydrolyzed to Compound 3E and the corresponding chiral Compound 4E.
- the chiral Compound 4E obtained through hydrolysis can be compared with a standard chiral sample of Compound 4E to determine the chiral purity of the chiral Compound 5E.
- the determination can be conducted by using a chiral HPLC.
- hippocampal neurons were isolated from embryological day 16 mice and seeded in 96-well tissue culture plates under conditions in which they degenerated in the absence of neurotrophin receptor ligands. Neuronal degeneration was assessed using morphological criteria 48 hours following cell seeding.
- the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) served as positive controls.
- the maximum cell death preventing activity of BDNF is defined as 100% neurotrophic activity.
- the efficacy of NGF is 80% of that of BDNF.
- the neurotrophic activity of the test compounds at each applied concentration was quantitated in terms of a percentage of the maximum BDNF-supported survival level. In the presence of culture medium (CM) and the absence of BDNF or compounds, survival is approximately 40% of the BDNF maximum effect and this is regarded as baseline survival. For each compound, dose-response curves were generated and the EC 50 and maximum survival percentage are derived.
- the compounds prepared and characterized as disclosed herein showed an EC 50 between about 1 nM and about 25 nM as well as a maximum efficacy between about 20% and about 100% of that of BDNF. Materials and Methods for Examples 34-40
- Polyclonal rabbit anti-NGF antibody was obtained from Chemicon (Temecula, California, United States of America). Monoclonal anti-phospho- ERK ⁇ 202/Y204 3 polyclonal anti-ERK42/44, monoclonal anti-phospho-AKT S473 , polyclonal anti-AKT, polyclonal anti-phospho-NF ⁇ B-p65(Ser 563 ), and site-specific polyclonal anti-Trk Y490 were obtained from Cell Signaling Technology, Inc. (Beverly, Massachusetts, United States of America). Monoclonal anti-NF ⁇ B-p65 was obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, California, United States of America).
- Monoclonal anti-actin was obtained from Sigma- Aldrich Corp. (St. Louis, Missouri, United States of America).
- Polyclonal TrkA and TrIdB antibodies were obtained from Upstate USA, Inc. (Charlottesville, Virginia, United States of America).
- Anti-pan-Trk 1087 and 1088 were previously characterized (Zhou, Holtzman, D.M., Weiner, R.I., Mobley, W.C. (1994) Proc Natl Acad Sci USA 91, 3824) and obtained from Dr. William C. Mobley (Stanford University, California, United States of America).
- p75 NTR polyclonal rabbit antibodies 9651 (Huber, L.J., Chao, M.V.
- Hippocampal neurons were prepared from E 16- 17 mouse embryos as previously described (Yang, T. et al. (2003) J Neurosci 23, 3353-3363). Low density cultures were initiated in poly-L-lysine coated A/2 plates by adding 25 ⁇ l of cell suspension (2000 neurons/well; 12,500 cells/cm 2 ), 25 ⁇ l of DMEM containing 10% FBS, and different concentrations of recombinant BDNF, NGF, or p75-binding compounds to each well. For studies employing p75 NTR+/+ and. p75 NTR"A neurons, mice carrying a mutation in exon 3 of the p75 NTR gene (Lee, K.F. et al.
- LY294002 obtained from EMD Biosciences/Calbiochem, San Diego, California, United States of America
- SN50 obtained from Alexis Corp., Lausen, Switzerland
- p75 TR antisera and control non-immune serum were used at a final dilution of 1:100 in the presence of BDNF, NGF, or p75-binding compounds.
- p75 NTR antibodies or p75 NTR"/" neurons survival was assessed at 48 hours.
- hippocampal neurons derived from E 16- 17 mice were cultured in poly-L-lysine coated six- well plates (Corning, Inc., Corning, New York, United States of America) in DMEM containing 10% FBS, followed by incubation in serum-free DMEM for 2 hours before addition of neurotrophins or compounds.
- neurons were harvested in lysis buffer consisting of: 20 mM Tris, pH 8.0, 137 raM NaCl, 1% Igepal CA-630, 10% glycerol, 1 mM PMSF, 10 ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin, 500 ⁇ M orthovanadate (Zhou, J., Valletta, J.S., Grimes, MX., Mobley, W.C. (1995) J Neurochem 65, 1146-1156).
- NGF ELISA was performed as previously described (Longo, F.M. et al. (1999) JNeurosci Res 55, 230-237). Briefly, 96-well plates were incubated with 0.1 pmol (at 1 nM) of p75/Fc or TrkA/Fc recombinant protein obtained from R&D System (Minneapolis, Minnesota, United States of America) overnight at 4 0 C followed by incubation with blocking buffer for 1 hour at room temperature. ProNGF at 100 ng/ml or different concentrations of NGF, and p75-binding compounds were diluted in sample buffer, added to the wells, and incubated for 6 hours with shaking at room temperature.
- TBS Tris-buffered saline
- anti- NGF rabbit polyclonal antibody overnight at 4 0 C.
- wells were incubated for 2.5 hours at room temperature with anti-rabbit IgG HRP conjugate and washed five times.
- 3,3',5,5'-tetramethyl-benzidine substrate was added and the optical density measured at 450 nm.
- NIH3T3 fibroblasts expressing either null vector or p75 NTR were obtained from Dr. William Mobley (Stanford University, California, United States of America). Cells were grown in monolayers, harvested in PBS with 2 mM EDTA, pelleted, and resuspended in ice-cold DMEM HEPES with 1 mg/ml BSA. 6-9 x 10 6 cells from one confluent 6-well plate were used for each experimental point.
- p75 NTR antibody (1 : 100) was allowed to bind in the presence or absence of 100 nM p75-binding compounds for 90 minutes at 4 0 C with gentle rotation, followed by four washes in PBS. The final cell pellet was resuspended in lysis buffer.
- Cortical oligodendrocytes from rat pups were prepared as previously described (Yoon et al. (1998) J Neurosci 18, 3273-3281, Harrington, A. W., Kim, J.Y., Yoon, S.O. (2002) J Neurosci 22, 156-166). Cells were treated with recombinant, cleavage-resistant proNGF at 0.05 nM (2.8 ng/ml). Controls were treated with equivalent volumes of proNGF purification buffer containing 350 mM imidazole. 24 hours after treatment, the cells were fixed and processed for MBP and TUNEL staining as previously described (Beattie, M.S. et al. (2002) Neuron 36, 375-386). 200-250 cells were counted per well, for a minimum of 600 cells per experimental condition.
- top maximal signal
- bottom basal signal
- [C] compound concentration
- S Schild coefficient
- HillSlope Hill coefficient
- [NGF] NGF concentration
- EC 50 concentration of NGF resulting in 50% maximal (top-bottom) binding
- a 2 concentration of compound resulting in a doubling of the EC 5O from the unshifted curve.
- the calculated Hill slope ranged from 1.0 to 1.6 and was generally not significantly different from 1.
- Example 35 Compounds Promote Hippocampal Neuron Survival [00357] High-throughput virtual screening based on neurotrophin loop 1 models and small-scale in vitro bioassays were used to identify chemically diverse compounds with potent neurotrophic activity (Figure 1). Approximately 800,000 compounds were screened in silico to produce a high yield of 4 positives out of 23 compounds submitted to in vitro screening (17%).
- Compound (iv) was prioritized, as preliminary studies indicated that it exhibits significant oral uptake and blood-brain barrier penetration.
- the relatively inactive Compound (v) was chosen as a negative control due to its structural similarity to Compound (iii) ( Figure 2a).
- Example 36 Compounds Interact with and work through p75 Receptors not Trk Receptors
- the EC 50 value for its biologic effect is approximately 15O pM, while its A 2 is nearly four orders of magnitude greater.
- Large differences between biologic potency of small molecules and binding estimated by ligand displacement are common (Lutz, M., and Kenakin, T. (1999) Quantitative Molecular Pharmacology and Informatics in Drug Discovery (Hoboken, New Jersey: John Wiley & Sons)), and may have several causes, including: differences between receptor states in binding versus functional assays; post-receptor signal amplification, such that maximal biologic effects are seen at very low receptor occupancies; partial displacement of a multivalent ligand by a smaller antagonist; and that the compound works through a mechanism independent of the targeted receptor.
- Trk activation it was of interest to determine whether the p75-binding compounds promote Trk activation.
- Compound (iii) and Compound (iv) were assessed for the ability to activate Trk autophosphorylation, as indicated by Trk Y490 phosphorylation, a well-established marker of Trk activation.
- Trk Y490 phosphorylation a well-established marker of Trk activation.
- BDNF exposure resulted in robust Trk activation (Figure 3i), while no activation was detected with NGF or the p75-binding compounds.
- the lack of signal with NGF ⁇ confirms that these cultures produce little or no TrkA and supports the idea that the trophic effects of NGF are mediated principally by p75 NTR .
- Pro-survival signaling associated with p75 NTR actions include activation of P13K and AKT (Roux, P.P., Bhakar, A.L., Kennedy, T.E., Barker, P.A. (2001) J Biol Chem 276, 23097-23104; Lachyankar, M.B., et al. (2003) J Neurosci Res 71, 157-172), NFKB (Mamidipudi, V., Li, X., Wooten, M. W. (2002) J Biol Chem 277, 28010-28018; Carter, B.D., et al.
- the ERK inhibitor PD98059 significantly decreased BDNF-stimulated survival while it had a small but significant effect on NGF activity, and produced no significant decrease in survival promoted by either Compound (iii) or Compound (iv) ( Figure 4e).
- Example 38 Compound (iii) and Compound (iv) do not promote cell death of mature oligodendrocytes, but inhibit pro-NGF-induced death
- NGF and the p75-binding compounds promoted cell survival in the hippocampal cultures used in the studies herein, liganding of p75 NTR by mature NGF or proNGF, has been associated with cell death rather than promotion of survival in certain cell types (Lee, R., Kermani, P, Teng, K.K., Hempstead, B. L. (2001) Science 294, 1945-1948; Casaccia-Bonnefil, P., Carter, B.D., Dobrowsky, R.T., Chao, M.V. (1996) Nature 386, 716-719).
- oligodendrocytes express p75 NTR but not TrkA, and undergo apoptotic death on treatment with NGF or proNGF (Beattie, M.S., et al. (2002) Neuron 36, 375-386; Casaccia-Bonnefil, P., Carter, B.D., Dobrowsky, R.T., Chao, M.V.
- proNGF binding to p75 NTR was assessed over a concentration range of 1500 nM to 10,000 nM.
- Compound (iii) and Compound (iv) inhibited proNGF binding equally, up to an approximately 30% decrement at the highest concentration (Figure 5b).
- proNGF-p75 NTR interaction may be more susceptible than in the in vitro assay to disruption by the p75-binding compounds; 2) at low concentrations, the compounds qualitatively alter proNGF binding to decrease the induction of cell death, but do not decrease the total amount of proNGF binding to decrease the induction of cell death but do not decrease the total amount of proNGF binding; or 3) that the compounds induce preferential activation of pro-survival signaling by p75 NTR without affecting proNGF binding.
- co-receptors e.g., sortilin
- Preferential survival pathway activation could result from differences in the way the compounds modulate receptor structure, as well as lack of binding to co-receptors expressed by oligodendrocytes, such as sortilin. Indeed, prior studies suggest that engagement of both sortilin and p75 NTR by proNGF promotes efficient ligand binding, receptor complex activation and apoptotic actions (Nykjaer, A., Willnow, T.E., and Petersen, CM. (2005) Curr Opin Neurobiol 15, 49-57).
- Example 39 Compound (iii) Blocks A ⁇ -Induced Neural Degeneration
- a ⁇ was preincubated for 3 days in water to allow formation of oligomers. El 7 hippocampal neurons were incubated for 5 days to allow for maturation prior to addition of A ⁇ with test compounds. Mature neurons demonstrate high A ⁇ vulnerability.
- Addition of A ⁇ 42-1 (30 ⁇ M) as a negative control caused no cell death. Addition of A ⁇ 1-42 at 10 ⁇ M or 30 ⁇ M caused an approximate 40% loss of neurons after a 3 day exposure ( Figure 6a). The results are similar to in vitro A ⁇ -induced death levels reported previously (Michaelis, M.L., et at.
- Data are expressed as percentage surviving cells over total cells present in a given measurement area. Mean +/- SE is shown with at least 20 areas measured per condition over multiple bioassays.
- the ability of Compound (iv) to entirely block A ⁇ -induced degeneration at low nanomolar concentrations, its favorable molecular weight (less than 500), and a favorable Lipinski score indicate that it is a high priority lead compound for preclinical development in in vivo AD models.
- Compound (iv) has also been shown to block A ⁇ -induced degeneration of cortical and septal neurons.
- Example 40 Compound (iv) Prevents Hair Loss in Middle Aged Mice
- the presence of age-related hair loss was demonstrated in 3 of 5 vehicle-treated mice and in 0 of 5 Compound (iv)-treated male mice.
- 4 of 10 vehicle-treated and 0 of 9 Compound (iv)- treated middle-aged male mice at the 2-month time point demonstrated hair loss.
- these studies indicate that 7 of 15 vehicle-treated, and 0 of 14 Compound (iv)-treated mice demonstrate hair loss.
- the resulting p value is 0.001 (Fisher's Exact test), supporting the presence of a significant effect in the preclinical studies.
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