CA2317505A1 - Enzyme catalyzed therapeutic agents - Google Patents

Enzyme catalyzed therapeutic agents Download PDF

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CA2317505A1
CA2317505A1 CA002317505A CA2317505A CA2317505A1 CA 2317505 A1 CA2317505 A1 CA 2317505A1 CA 002317505 A CA002317505 A CA 002317505A CA 2317505 A CA2317505 A CA 2317505A CA 2317505 A1 CA2317505 A1 CA 2317505A1
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cell
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CA2317505C (en
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H. Michael Shepard
Michael P. Groziak
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KIADIS PHARMA INTELLECTUAL PROPERTY BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A61K47/556—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells enzyme catalyzed therapeutic agent [ECTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A61K47/67—Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Crystallography & Structural Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

This invention provides a method for identifying potential therapeutic agents by contacting a target cell with a candidate therapeutic agent which is a selective substrate for an endogenous, intracellular enzyme in the cell which is enhanced in its expression as a result of selection by biologic or chemotherapy. This invention also provides methods and examples of molecules for selectively killing a pathological cell by contacting the cell with a prodrug that is a selective substrate for an endogenous, intracellular enzyme. The prodrug is subsequently converted to a cellular toxin. Further provided by this invention is a method for treating a pathology characterized by pathological, hyperproliferative cells in a subject by administering to the subject a prodrug that is a selective substrate for an endogenous, overexpressed, intracellular enzyme, and converted by the enzyme to a cellular toxin in the hyperproliferative cell.

Claims (55)

1. A method for identifying potential therapeutic agents, comprising:
(a) contacting a target cell with a candidate therapeutic phosphoryl or phosphoramidate prodrug that is a selective substrate for a target enzyme, under conditions that favor the incorporation of the agent into the intracellular compartment of the target cell;
(b) assaying the target cell for inhibition of cellular proliferation or cell killing.
2. The method of claim 1, wherein the prodrug is a phosphoramidate derivative of 2'-deoxyuridine.
3. A method for identifying potential therapeutic agents, comprising:
(a) contacting a target cell with a candidate therapeutic phosphoryl or phophoramidate prodrug having a detectably labeled toxic leaving group and that is a selective substrate for a target enzyme, under conditions that favor the incorporation of the agent into the intracellular compartment of the target cell;
(b) assaying the culture media for the amount of label released and comparing it to the amount of label released.
4. The method of claim 3, wherein the prodrug is a phosphoramidate derivative of 2'-deoxyuridine.
5. The method of any of claims 1 to 5, wherein the target cell is characterized as resistant to a chemotherapeutic drug.
6. The method of any of claims 1 to 5, wherein the target enzyme is amplified as a result of selection in vivo by chemotherapy.
7. The method of any of claims 1 to 5, wherein the target enzyme is an endogenous intracellular enzyme that is overexpressed in the target cell.
8. The method of any of claims 1 to 5, wherein the target enzyme is thymidylate synthase.
9. A method for inhibiting the proliferation of a hyperproliferative cell, comprising contacting the cell with a phosphoryl or phorphoramidate prodrug that is selectively converted to a toxin in the cell by an endogenous, intracellular enzyme.
10. A method for treating a pathology characterized by hyperproliferative cells in a subject comprising administering to the subject a phosphoryl or phosphoramidate prodrug that is converted to a toxin in a hyperproliferative cell by an intracellular enzyme that is endogenously overexpressed or over-accumulated in the cell.
11. The method of any of claims 9 or 10, wherein the candidate therapeutic agent is an L- or D- compound of the formula:
wherein R1 is or contains a chemical entity that has a molecular dimension and electrophilicity compatible with extraction from the pyrimidine ring by thymidylate synthase, and which upon release from the pyrimidine ring by thymidylate synthase has the ability to inhibit the proliferation of the cell or kill the cell; or a compound of the formula:

wherein n is an integer from 0 to 10; wherein A is a phosphoryl or phosphoramide derivative, or a compound of the formula:
wherein Q is a phosphoryl or phosphoramidate derivative containing a chemical entity selected from the group consisting of sugar groups, thio-sugar groups, carbocyclic groups, and derivatives thereof.
12. The method of claim 11, wherein Q has the formula:
wherein R7 is selected from the group consisting of phosphoryl, phosphoramidate and derivatives thereof, and wherein R2 and R3 are the same or different and are independently -H
or -OH.
13. The method of claim 11, wherein R1 is a halogen.
14. The method of claim 11, wherein R1 is an alkyl group, i.e., (-CH=CH)n-R4, wherein n is an integer from 0 to 10, and R4 is selected from the group consisting of H, a halogen, alkyl, alkene, alkyne, hydroxy, -O-alkyl, -O-aryl, O-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -NH2, -NH-alkyl, -N(alkyl)2, -NHCHO, a cyanide, cyanate and thiocyanate cyanide, cyanate and thiocyanate halovinyl compound, a halomercuric compound, -NHOH, -NHO-alkyl, and NHNH2.
15. A compound of the formula:
wherein:
R1 is a moiety of the formula:
R2 is a divalent electron conduit moiety selected from the group consisting of:
an unsaturated hydrocarbyl group;

an aromatic hydrocarbyl group comprising one or more unsaturated hydrocarbyl groups; and, a heteroaromatic group comprising one or more unsaturated hydrocarbyl groups;
R3 is a divalent spacer moiety selected from the group consisting of:
R5 may be the same or different and is independently a linear or branched alkyl group having from 1 to 10 carbon atoms, or a cycloalkyl group having from 3 to 10 carbon atoms;
n is an integer from 0 to 10;
m is 0 or 1;
R4 is a toxophore moiety selected from the group consisting of:
X is -Cl, -Br, -I, or other potent leaving group, with the provisio that when R7 is -H, and M is zero, then R4 is not a halogen or when m is zero and n is zero, then R4 is not a halogen;
Y is independently -H or -F;
Z is independently -O- or -S-;
Q is a sugar moiety selected from the group consisting of:
R6 is independently -H, -OH, -OC(=O)CH3, or other protected hydroxyl group; and, R7 is hydrogen, a phosphate group, or a phosphoramidate group;
and wherein said compound may be in any enantiomeric, diasteriomeric, or stereoisomeric form, including, D-form, L-form, .alpha.-anomeric form, and .beta.-anomeric form.
16. A compound according to claim 15, wherein Q is:
17. A compound according to claim 15, wherein Q is:
18. A compound according to any one of claims 15 to 17, wherein R3 is a divalent spacer moiety selected from the group consisting of:
19. A compound according to any one of claims 15 to 17, wherein R2 is an unsaturated hydrocarbyl group selected from the group consisting of:
20. A compound according to any one of claims 15 to 17, wherein R2 and R3, taken together form a structure selected from the group consisting of:
21. A compound according to any one of claims 15 to 17, wherein R2 is an aromatic hydrocarbyl group selected from the group consisting of:
22. A compound according to any one of claims 15 to 17, wherein R2 is a heteroaromatic group selected from the group consisting of:
wherein J is -O-, -S-, -Se-, -NH-, or -NR ALK-, wherein R ALK is a linear or branched alkyl having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms.
23. A compound according to any one of claims 15 to 22, wherein R7 is selected from the group consisting of:
24. A compound according to any one of claims 15 to 22, wherein R7 is selected from the group consisting of:
25. A compound according to any one of claims 15 to 22, wherein R7 is selected from the group consisting of:
26. A compound according to any one of claims 15 to 22, wherein R7 is selected from the group consisting of:
27. A compound according to any one of claims 15 to 22, wherein R4 is selected from the group consisting of:
28. A compound according to any one of claims 15 to 27, wherein R4 is selected from the group consisting of:
29. A compound according to any one of claims 15 to 27, wherein R4 is:
30. A compound according to any one of claims 15 to 27, wherein R4 is:
31. A compound according to any one of claims 15 to 27, wherein R4 is:
32. A compound according to any one of claims 15 to 27, wherein R4 is:
33. A compound according to any one of claims 15 to 27, wherein R4 is:
34. A compound according to any one of claims 15 to 27, wherein R4 is:
35. A compound of the formula:
36. A compound of the formula:
37. A compound of the formula:
38. A compound of the formula:
39. A compound of the formula:
40. A method of forming a compound of the formula:
wherein "Base" denotes a nucleic acid base;
which method comprises the step of reacting a compound of the formula:
with a compound of the formula:
in the presence of an HCl scavenger.
41. A method of forming a compound of the formula:
wherein R1 is a substituent;
which method comprises the step of reacting a compound of the formula:
with a compound of the formula:
in the presence of an HCl scavenger.
42. The method according to claim 40 or 41, wherein said HCl scavenger is imidazole.
43. The method according to any one of claims 40 to 42, wherein said reaction is performed in a non-aqueous solvent comprising dimethylformamide.
44. A method for screening for a therapeutic agent, comprising:
(a) contacting a first target cell with a compound of any of claims 15 or 37 to 39, under conditions that favor the incorporation of the compound into the intracellular compartment of the target cell and a second target cell with a potential therapeutic agent, under conditions that favor the incorporation of the compound into the intracellular compartment of the target cell; and (b) assaying the second target cell for inhibition of cellular proliferation or cell killing.
45. The method of claim 44, wherein the target cell is characterized as resistant to a chemotherapeutic drug.
46. The method of claim 44, wherein the target cell is characterized as expressing a target enzyme that is amplified as a result of selection in vivo by chemotherapy.
47. The method of claim 46, wherein the target enzyme is an endogenous intracellular enzyme that is overexpressed in the target cell.
48. The method of claim 47, wherein the endogeneous overexpression of an intracellular enzyme is the result of amplification of the gene coding for the enzyme.
49. The method of claim 47, wherein the enzyme is thymidylate synthase.
50. Use of a compound of any of any of claims 15 or 37 to 39, for the preparation of a medicament to treat inhibit the proliferation of a cell.
51. A method for inhibiting the proliferation of a hyperproliferative cell, comprising contacting the cell with an effective amount of a compound of any of claims 15 or 37 to 39.
52. The method of claim 66, wherein the hyperproliferative cell is characterized by the endogenous overexpression of an intracellular enzyme.
53. The method of claim 52, wherein the enzyme is thymidylate synthase.
54. A method for treating a pathology characterized by hyperproliferative cells in a subject comprising administering to the subject a compound of any of claims 15 or 37 to 39.
55. A method for screening for a therapeutic agent, comprising contacting a target cell with a compound of any of claims 15 or 37 to 39, wherein R4 is:
which target cell favor the incorporation of the compound into the target cell, for the diagnostic purpose of detecting intracellular levels of thymidylate synthase.
CA2317505A 1998-01-23 1999-01-22 Enzyme catalyzed therapeutic agents Expired - Lifetime CA2317505C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US7226498P 1998-01-23 1998-01-23
US7695098P 1998-03-05 1998-03-05
US10863498P 1998-11-16 1998-11-16
US60/076,950 1998-11-16
US60/072,264 1998-11-16
US60/108,634 1998-11-16
PCT/US1999/001332 WO1999037753A1 (en) 1998-01-23 1999-01-22 Enzyme catalyzed therapeutic agents

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CA2317505A1 true CA2317505A1 (en) 1999-07-29
CA2317505C CA2317505C (en) 2011-01-04

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US (3) US6339151B1 (en)
EP (2) EP1167972B1 (en)
JP (2) JP2002500880A (en)
CN (1) CN1192102C (en)
AT (1) ATE212661T1 (en)
AU (1) AU753155B2 (en)
BR (1) BR9907736A (en)
CA (1) CA2317505C (en)
DE (1) DE69900841T2 (en)
DK (1) DK1045897T3 (en)
ES (1) ES2172303T3 (en)
HK (2) HK1039520A1 (en)
IL (1) IL137164A0 (en)
PT (1) PT1045897E (en)
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WO (1) WO1999037753A1 (en)

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