Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-02
2002-03-12
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S011400, C514S014800, C514S015800, C514S016700, C514S017400, C530S311000, C530S317000, C530S327000, C530S328000, C530S329000, C530S330000
Reexamination Certificate
active
06355613
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to conformationally constrained N
&agr;
backbone-cyclized somatostatin analogs cyclized via novel linkages, and to pharmaceutical compositions containing same.
BACKGROUND OF THE INVENTION
Somatostatin Analogs
Somatostatin is a cyclic tetradecapeptide found both in the central nervous system and in peripheral tissues. It was originally isolated from mammalian hypothalamus and identified as an important inhibitor of growth hormone secretion from the anterior pituitary. Its multiple biological activities include inhibition of the secretion of glucagon and insulin from the pancreas, regulation of most gut hormones and regulation of the release of other neurotransmitters involved in motor activity and cognitive processes throughout the central nervous system (for review see Lamberts,
Endocrine Rev
., 1988, 9, 427). Additionally, somatostatin and its analogs are potentially useful antiproliferative agents for the treatment of various types of tumors.
Natural somatostatin (also known as Somatotropin Release Inhibiting Factor, SRIF) of the following structure:
H-Ala
1
-GlY
2
-Cys
3
-Lys
4
-Asn
5
-Phe
6
-Phe
7
-Trp
8
-Lys
9
-Thr
10
-Phe
11
-Thr
12
-Ser
13
-Cys
14
-OH
was first isolated by Guillemin and colleagues (Bruzeau et al.
Science
, 1973, 179, 78). It exerts its effect by interacting with a family of receptors. Recently, five receptor subtypes, termed SSTR1-5, have been identified and cloned. In its natural form, somatostatin has limited use as a therapeutic agent since it exhibits two undesirable properties: poor bioavailability and short duration of action. For this reason, great efforts have been made during the last two decades to find somatostatin analogs that will have superiority in either potency, biostability, duration of action or selectivity with regard to inhibition of the release of growth hormone, insulin or glucagon.
Structure-activity relation studies, spectroscopic techniques such as circular dichroism and nuclear magnetic resonance, and molecular modeling approaches reveal the following: the conformation of the cyclic part of natural somatostatin is most likely to be an antiparallel &bgr;-sheet; Phe
6
and Phe
11
play an important role in stabilizing the pharmacophore conformation through hydrophobic interactions between the two aromatic rings; the four amino acids Phe
7
-Trp
9
-Lys
9
-Thr
10
which are spread around the &bgr;-turn in the antiparallel &bgr;-sheet are essential for the pharmacophore; and (D)Trp
8
is preferable to (L)Trp
8
for the interactions with somatostatin receptor subtypes 2 through 5.
Nevertheless, a hexapeptide somatostatin analog containing these four amino acids anchored by a disulfide bridge:
is almost inactive both in vitro and in vivo, although it has the advantage of the covalent disulfide bridge which replaces the Phe5-Phe
11
hydrophobic interactions in natural somatostatin.
Four main approaches have been attempted in order to increase the activity of this hexapeptide somatostatin analog. (1) Replacing the disulfide bridge by a cyclization which encourages a cis-amide bond, or by performing a second cyclization to the molecule yielding a bicyclic analog. In both cases the resultant analog has a reduced number of conformational degrees of freedom. (2) Replacing the original residues in the sequence Phe
7
-(D)Trp
8
-Lys
9
-Thr
10
with other natural or non-natural amino acids, such as replacing Phe
7
with Tyr
7
and Thr
10
with Val
10
. (3) Incorporating additional functional groups from natural somatostatin with the intention that these new elements will contribute to the interaction with the receptor. (4) Eliminating one of the four amino acids Phe
7
-(D)Trp
8
-Lys
9
-Thr
10
with the assumption that such analogs would be more selective.
The somatostatin analog, MK-678:
cyclo(N-Me-Ala
6
-Tyr
7
-(D)Trp
8
-Lys
9
-Val
10
-Phe)
is an example of a highly potent somatostatin analog designed using the first three approaches above (Veber, et al.,
Life Science
, 1984, 34, 371). In this hexapeptide analog, a cis-amide bond is located between N-Me-Ala and Phe
11
, Tyr
7
and Val
10
replace Phe
7
and Thr
10
respectively, and Phe
11
is incorporated from natural somatostatin.
Another group of somatostatin analogs (U.S. Pat. Nos. 4,310,518 and 4,235,886) includes Octreotide:
the only approved somatostatin analog currently available. It was developed using the third approach described above. Here, (D)Phe
5
and the reduced C-terminal Thr
12
-CH
2
OH are assumed to occupy some of the conformational space available to the natural Phe
6
and Thr
12
, respectively.
The compound TT-232:
is closely related to Octreotide and is an example of implementing the fourth approach described above. The lack of Thr
10
is probably responsible for its high functional selectivity in terms of antitumor activity.
These examples of highly potent somatostatin analogs suggest that the phenylalanines in positions 6 and 11 not only play an important role in stabilizing the pharmacophore conformation but also have a functional role in the interaction with the receptor. It is still an open question whether one phenylalanine (either Phe
6
or Phe
11
) is sufficient for the interaction with the receptor or whether both are needed.
It is now known that the somatostatin receptors constitute a family of five different receptor subtypes (Bell and Reisine,
Trends Neurosci
., 1993, 16, 34-38), which may be distinguished on the basis of their tissue specificity and/or biological activity. Somatostatin analogs known in the art may not provide sufficient selectivity or receptor subtype selectivity, particularly as anti-neoplastic agents (Reubi and Laissue,
TIPS
, 1995, 16, 110-115).
Symptoms associated with metastatic carcinoid tumors (flushing and diarrhea) and vasoactive intestinal peptide (VIP) secreting adenomas (watery diarrhea) are treated with somatostatin analogs. Somatostatin has been also approved for the treatment of severe gastrointestinal hemorrhages. Somatostatin may also be useful in the palliative treatment of other hormone-secreting tumors (e.g., pancreatic islet-cell tumors and acromegaly) and hormone dependent tumors (e.g., chondrosarcoma and osteosarcoma) due to its antisecretory activity.
Improved Peptide Analogs
As a result of major advances in organic chemistry and in molecular biology, many bioactive peptides can now be prepared in quantities sufficient for pharmacological and clinical utilities. Thus in the last few years new methods have been established for the treatment and therapy of illnesses in which peptides have been implicated. However, the use of peptides as drugs is limited by the following factors:. a) their low metabolic stability towards proteolysis in the gastrointestinal tract and in serum; b) their poor absorption after oral ingestion, in particular due to their relatively high molecular mass or the lack of specific transport systems or both; c) their rapid excretion through the liver and kidneys; and d) their undesired side effects in non-target organ systems, since peptide receptors can be widely distributed in an organism.
It would be most beneficial to produce conformationally constrained peptide analogs overcoming the drawbacks of the native peptide molecules, thereby providing improved therapeutic properties.
A novel conceptual approach to the conformational constraint of peptides was introduced by Gilon, et al., (
Biopolymers
, 1991, 31, 745) who proposed backbone to backbone cyclization of peptides. The theoretical advantages of this strategy include the ability to effect cyclization via the carbons or nitrogens of the peptide backbone without interfering with side chains that may be crucial for interaction with the specific receptor of a given peptide. While the concept was envisaged as being applicable to any linear peptide of interest, in point of fact the limiting factor in the proposed scheme was the availability of suitable building units that must be used to replace the amino acids that are to be linked via bridging groups. The actual reduction to practice o
Afargan Mich El M.
Gellerman Gary
Hornik Vered
Gupta Anish
Low Christopher S. F.
Peptor Limited
Winston & Strawn
LandOfFree
Conformationally constrained backbone cyclized somatostatin... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Conformationally constrained backbone cyclized somatostatin..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Conformationally constrained backbone cyclized somatostatin... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2860851