1. A neurotrophin receptor agonist or antagonist pharmaceutical composition comprising an acceptable neurotrophin receptor agonistic amount of a neutrophin mimicking -turn peptidomimetic cyclic compound, in association with a pharmaceutically acceptable carrier.
2. A composition according to claim 1, wherein said compound has a macrocyclic ring of 13 to 17 ring atoms.
3. A composition according to claim 1 or 2, wherein said compound has one or more side chains on said macrocyclic ring, which one or more side chains extend from backbone ring atoms.
4. A composition according to claim 3, wherein said one or more, side chains correspond to residues found within -turns of a neurotrophin.
5. A composition according to claim 4, wherein said neurotrophin is nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-45 (NT45), or brain derived neurotrophic factor (BDNF).
6. A composition according to claim 4, wherein said neurotrophin binds to a receptor.
7. A composition according to claim 4, wherein said neurotrophin receptor is TrkA, TrkB, TrkC or p75.
8. A composition according to claim 1, wherein said cyclic compound is a -turn peptidomimetric cyclic compound of formula (I)
26
wherein
R1 and R3 are selected from alkyl or aryl substituents found in a natural or unnatural amino acid;
R2 and R4 are hydrogen or alkyl;
R5 and R6 are hydrogen; or
R1 and R2 or R3 and R4 can together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, and
Z, Y, X, LINKER and n are as defined herein.
9. A composition according to claim 1, wherein said compound is selected from
27
28
29
10. A method of treating or preventing a neurotrophin receptor mediated disorder in a patient comprising administering to a patient in need, an acceptable neurotrophin receptor agonistic or antagonistic amount of a neurotrophin mimicking -turn peptidomimetic cyclic compound.
11. Use of -turn peptidomimetic cyclic compounds in evaluating structural requirements of neutrophin mimicking -turn peptidomimetic cyclic compounds.
12. Use of a neurotrophin mimicking -turn peptidomimetic cyclic compound in the manufacture of a medicament for treating or preventing a neurotrophin receptor mediated disorder.
13. Use of claim 12, wherein said compound is selected from
30
31
32
14. A -turn peptidomimetic cyclic compound of formula (I)
33
wherein
R1 and R3 are selected from alkyl or aryl substituents found in a natural or unnatural amino acid;
R2 and R4 are hydrogen or alkyl;
R5 and R6 are hydrogen; or
R1 and R2 or R3 and R4 can together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, and
Z, Y, X, LINKER and n are as defined herein.
15. A cyclic compound of claim 14, in which the macrocyclic ring containing X has 13 to 17 ring atoms.
16. A cyclic compound of claim 15, having one or more side chains on said macrocyclic-ring, which one or more side chains extend from backbone ring atoms.
17. A compound of claim 14, 15 or 16, wherein R1 and R3 are derived from a sequence of different amino acids side chains selected from natural and synthetic amino acids.
18. A compound of claim 14, 15, 16 or 17, wherein X is O, S or NH.
19. A compound of claim 14 formula
34
20. A compound of claim 14 formula:
35
21. A compound of claim 14, selected from
36
37
38
22. A method of screening andor evaluating necessary structural requirements of agonists and antagonists for neurotrophin receptors which exploits a cyclic compound as defined in any one of claims 14 to 21 in competition with a test compound under investigation.
23. Use of a compound as defined in any one of claims 14 to 21 for identifying functionally important receptor domains, in binding assays.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1-24. (canceled)
25. An implant for insertion into a body lumen, the implant comprising:
a first tubular medical device having a tubular body extending along an axis and a plurality of slits extending through a sidewall thereof to form a plurality of first sidewall segments such that radial expansion of the first medical device forms an alternating pattern of flared first sidewall segments and first slits disposed adjacent the body vessel wall; and
a second tubular medical device having a second tubular body and a plurality of slits extending through a sidewall thereof to form a plurality of second sidewall segments such that radial expansion of the second medical device forms an alternating pattern of flared second sidewall segments and second slits, the second tubular medical device disposed coaxially within the within first tubular medical device and rotationally aligned with the first tubular medical device such that the flared second sidewall segments of the second tubular medical device at least partially cover the first slits disposed adjacent the body vessel wall of the first tubular medical device.
26. The implant of claim 25, wherein the tubular body of each of the first and second medical devices further includes a plurality of radiopaque markers disposed at one end and having a defined relationship to the number and position of the plurality of slits.
27. The implant of claim 25, wherein the plurality of slits of the first and the second tubular medical devices extend parallel to the axis.
28. The implant of claim 25, wherein the plurality of slits of the first and the second tubular medical devices are not parallel to the axis.
29. The implant of claim 25, wherein the plurality of slits are spaced equally about a perimeter of the first end of the tubular body of the first and the second tubular medical devices.
30. The implant of claim 28, wherein the plurality of slits are spaced unequally about a perimeter of the first end of the tubular body of the first and the second tubular medical devices.
31. The implant of claim 25, wherein the tubular body of the first and the second tubular medical devices comprises a plurality of struts forming a radially expandable cell pattern and the plurality of slits comprise a plurality of discontinuities in the cell pattern.
32. The implant of claim 25, further comprising a cover at least partially disposed about a portion of both the first and second tubular medical devices.
33. The implant of claim 25, wherein at least a portion of one of the first or the second tubular medical devices are adapted for placement in a renal vessel.
34. The implant of claim 25, wherein at least a portion of one of the first or the second tubular medical devices are adapted for placement in one of the ostial and aortic areas of a vessel.
35. The implant of claim 25, further including a third tubular medical device having a third tubular body and a plurality of slits extending through a sidewall thereof to form a plurality of third sidewall segments such that radial expansion of the third tubular medical device forms an alternating pattern of flared third sidewall segments and third slits, the third tubular medical device disposed coaxially within the within first and second tubular medical devices and rotationally aligned with the first and second tubular medical devices such that the flared third sidewall segments of the third tubular medical device at least partially cover the first and second slits disposed adjacent the body vessel wall of the first and second tubular medical devices.
36. An implant for insertion into a body lumen, the implant comprising:
first and second medical devices each having a tubular body having a length extending along an axis between first and second ends thereof, each tubular body having a sidewall with at least two slits extending therethrough from the first end toward the second end, the at least two slits extending less than the length of each tubular body, the at least two slits defining at least two sidewall segments having different radial expansion characteristics, relative to the axis, than a non-slitted portion of each tubular body, the second medical device disposed coaxially within the first medical device such that the at least two sidewall segments of the second medical device at least partially cover the at least two slits of the first medical device.