Anti-inflammatory medicaments

• US 20080064688A1
• Filed: 01/20/2006
• Published: 03/13/2008
• Est. Priority Date: 12/31/2002
• Status: Active Grant

• Current Assignee: Daniel L. Flynn, Peter A. Petillo
• Original Assignee: Daniel L. Flynn, Peter A. Petillo
• Inventors: Flynn, Daniel L., Petillo, Peter A.
• Granted Patent: US 7,531,566 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2601/10 : the ring being unsaturated
• CPC Class Codes: C07C 271/56 : with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 285/10 : 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.

Claims

1. A method of modulating the activation state of p38 α

-kinase comprising the step of contacting said kinase with a molecule having the formula

2. The method of claim 1, said contacting step occurring at the region of a switch control pocket of said kinase.

3. The method of claim 2, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (II) molecule.

4. The method of claim 2, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.

5. The method of claim 4, said region being selected from the group consisting of the α

-C helix, the α

-D helix, the catalytic loop, the switch control ligand sequence, the C-lobe residues, the glycine rich loop residues, and combinations thereof.

6. The method of claim 5, said α

-C helix including SEQ ID NO. 2.

7. The method of claim 5, said catalytic loop including SEQ ID NO. 3.

8. The method of claim 5, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.

9. The method of claim 5, said C-lobe residues including SEQ ID NO. 6.

10. The method of claim 5, said glycine rich loop residues including SEQ ID NO. 7.

11. The method of claim 1, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.

12. The method of claim 1, said activation state being selected from the group consisting of the upregulated and downregulated states.

13. The method of claim 1, said molecule being an antagonist of the on switch control pocket for said kinase.

14. The method of claim 1, said molecule being an agonist of the off switch control pocket for said kinase.

15. The method of claim 1, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron'"'"'s disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.

16. The method of claim 15, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

17. The method of claim 1, said molecule having the formula

18. A method of modulating the activation state of p38α

-kinase comprising the step of contacting said kinase with a molecule having the formula

A-T-(L)_n-(NH)_p-D-(E)_q-(Y)_t-Q 

 

(IB)

wherein;

Y is selected from the group consisting of —

O—

, —

S—

, —

NR₆—

, —

NR₆SO₂—

, —

NR₆CO—

, alkynyls, alkenyls, alkylenes, —

O(CH₂)_h—

, and —

NR₆(CH₂)_h—

, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —

O(CH₂)_h—

, and —

NR₆(CH₂)_h—

, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —

O(CH₂)_h—

the introduction of the side-chain oxo group does not form an ester moiety;

A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and

most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and

19. The method of claim 18, said contacting step occurring at the region of a switch control pocket of said kinase.

20. The method of claim 19, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (IB) molecule.

21. The method of claim 19, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.

22. The method of claim 21, said region being selected from the group consisting of the α

-C helix, the α

-D helix, the catalytic loop, the switch control ligand sequence, the C-lobe residues, the glycine rich loop residues, and combinations thereof.

23. The method of claim 22, said α

-C helix including SEQ ID NO. 2.

24. The method of claim 22, said catalytic loop including SEQ ID NO. 3.

25. The method of claim 22, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.

26. The method of claim 22, said C-lobe residues including SEQ ID NO. 6.

27. The method of claim 22, said glycine rich loop residues including SEQ ID NO. 7.

28. The method of claim 18, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.

29. The method of claim 18, said activation state being selected from the group consisting of the upregulated and downregulated states.

30. The method of claim 18, said molecule being an antagonist of the on switch control pocket for said kinase.

31. The method of claim 18, said molecule being an agonist of the off switch control pocket for said kinase.

32. The method of claim 18, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Chron'"'"'s disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.

33. The method of claim 32, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

34. A method of altering the biological activity of a p38 kinase comprising the steps of:

providing a p38-alpha kinase having a switch control pocket;

contacting said kinase with a non-naturally occurring molecule modulator; and

causing said modulator to bind with said kinase at the region of said pocket in order to at least partially regulate the biological activity of the kinase by inducing or restricting the conformation of the kinase.

35. The method of claim 34, said molecule serving to induce a conformation change in said kinase.

36. The method of claim 34, said molecule serving to restrict a conformation change in said kinase.

37. The method of claim 34, said kinase also having a switch control ligand, said ligand interacting in vivo with said pocket to regulate the conformation and biological activity of said kinase such that the kinase will assume a first conformation and a first biological activity upon said ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of said ligand-pocket interaction.

38. The method of claim 34, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an agonist.

39. The method of claim 34, said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an antagonist.

40. The method of claim 34, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an agonist.

41. The method of claim 34, said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an antagonist.