Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-28
2003-10-28
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S002600, C514S019300, C514S017400, C514S018700, C514S277000, C514S279000, C530S330000, C530S331000
Reexamination Certificate
active
06638941
ABSTRACT:
BACKGROUND OF THE INVENTION
Over the years, peptidomimetics have become immensely important for both organic and medicinal chemists, as well as the pharmaceutical industry due to the multitude of biological active peptides discovered and characterized. Peptidomimetics are currently exploited to overcome problems associated with their parent peptides (for review, see, e.g. reference 28). These improvements include increased selectivity, oral bioavailability and prolonging the activity by hindering enzymatic degradation within the organism. Among the class of peptidomimetics are the mimetics of protein secondary structure.
Retention of peptide secondary structure is an important tool in drug research when applied to fixing the active conformation of a protein. Constraining the structure of a peptide in its biologically active conformation increases its activity or binding. Within the realm of secondary structures are protein &bgr;-turns, which have attracted the attention of medicinal chemists due its importance in such events as hormone-receptor and peptide-enzyme recognition. The &bgr;-turn is a segment composed of four amino acids (i to i+1) that occurs when a peptide strand changes its direction. In areas, such as cellular signal transduction, protein-protein interactions are known to be crucial for proper signaling, and may find application for protein &bgr;-turn mimetics.
Cellular signal-transduction pathways that are initiated by transmembrane receptors associating with cytoplasmic protein kinases rely on two small protein domains containing sequences of 50-100 amino acids each. These sequences, referred to as Src homology 2 (SH2) and Src homology 3 (SH3) domains, can fold into modules which interact independently of their surrounding sequences. Because SH2 and SH3 domains are involved in protein-protein interactions in the signal transduction pathway, they represent potential targets for therapeutic drugs.
The nature of the interaction between SH3 domains and proteins has been the subject of recent study. The three-dimensional structure of SH3/peptide complexes have been extensively investigated (5-16). These reports revealed that SH3 domains interact with protein ligands via hydrophobic contacts on the surface of the domain and protein. These domains have preferences for certain sequences of amino acids, as determined by screening against peptide combinatorial libraries. The protein ligands form a polyproline type II (PPII) left-handed &agr;-helix containing a consensus sequence that can be generalized as XPpXP, where X is an aliphatic amino acid and p is preferably proline to maintain the helix.
All reported naturally-occurring SH3 ligands are peptides, although certain non-natural SH3 ligands have been described. A variety of peptidomimetics have been described, some of which mimic the &bgr;-turn motif (for a review, see, e.g., reference 28). However, no peptidomimetic has been reported to modulate activity of SH3 domains. In a study by Feng et al., a biased combinatorial library was constructed by functionalizing the N-terminus of a pentapeptide with various non-peptide elements, and the constructs were assayed for binding with Src SH3 domain (17). The nonpeptidic moieties appeared to interact with the specificity pocket of Src SH3 domain, lowering the k
d
almost 1000-fold from the parent pentapeptide (>1000 mM to 3.4 mM). However, to date, few if any non-peptidic ligands binding in the hydrophobic pockets of SH3 domains have been discovered.
The &bgr;-turn has attracted the attention of medicinal chemists due to its importance in such events as hormone-receptor and peptide-enzyme recognition. Rapid degradation of natural peptide substrate or ligands containing the &bgr;-turn have lead to the design of compounds mimicking this secondary structure (19, 24-28, 29). A tricyclic compound which includes a 5,6-spirolactam moiety has been described as a Type II &bgr;-turn mimetic (A. M. Khalil et al., 25th National Medicinal Chemistry Symposium, University of Michigan, 1996). The configuration of the compound so prepared is reported to provide a &bgr;-turn-type structure, rather than an extended conformation.
SUMMARY OF THE INVENTION
This invention pertains to peptide mimetics including peptide &bgr;-turn mimetics, to compositions which include the peptide &bgr;-turn mimetics of the invention, and to methods for inhibiting protein-protein interactions with SH3 domains.
In one aspect, the invention provides a compound represented by the formula (Formula I):
in which
R
1
is hydrogen, alkyl, aryl, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, or an amino acyl group (e.g., an amino acid residue or a peptide segment);
R
2
is hydrogen, alkyl, aryl, or —C(R
2a
)(R
2b
)C(O)R
5
;
R
2a
and R
2b
are each independently hydrogen, alkyl, or aryl; or, R
2a
and R
2b
, taken together with the carbon atom to which they are attached, form a 3 to 8 membered carbocyclic or heterocyclic ring;
R
3
and R
4
are each, independently for each occurrence, hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, cyano, or trifluoromethyl; or R
2a
and R
4
, together with the atoms to which they are attached, form a 5 or 6-membered heterocyclic ring;
R
5
is hydroxy, alkyl, aryl, amino, alkoxy, aryloxy, —SH, alkylthio, arylthio or an amino acyl group (e.g., an amino acid residue or a peptide segment);
m and n are each independently 1 or 2; or a salt thereof.
In a preferred embodiment, R
1
is a tetrapeptide, more preferably Ac-Pro-Arg-Pro-Leu or Ac-Ala-Pro-Ala-Leu. In another embodiment, R
1
is an amino acyl residue selected from the group consisting of Boc-Leu and Boc-Val. In still other embodiments, R
1
is an aminocarboxy moiety represented by the formula —C(O)NHR
7
, in which R
7
is an aryl moiety or a bulky alkyl group. In preferred embodiments, R
2
is a moiety represented by the formula —C(R
2a
)(R
2b
)C(O)R
5
. In preferred embodiments, R
2b
is hydrogen and R
2a
is a side-chain moiety of a naturally occurring amino acid. In preferred embodiments, R
5
is a tripeptide moiety selected from the group consisting of Lys-Pro-Pro-OH and Ala-Pro-Gly-OH. In preferred embodiments, R
3
is hydroxy.
In another embodiment, the invention provides a compound represented by the formula (Formula Ia):
in which
X is —CH
2
—, S or O;
R
1
is hydrogen, alkyl, aryl, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, or an amino acyl group;
R
2b
is hydrogen, alkyl, or aryl;
R
3
and R
4
are each, independently for each occurrence, hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, cyano, or trifluoromethyl;
R
5
is hydroxy, alkyl, aryl, amino, alkoxy, aryloxy, —SH, alkylthio, arylthio or an amino acyl group;
m and p are each, independently, 1 or 2; or a salt thereof;
with the proviso that if X is S, p is 1, and R
2b
is hydrogen, then the configuration at the carbon atom to which R
2b
is attached is not the R configuration.
In preferred embodiments, R
2b
is hydrogen.
In another aspect, the invention provides a method for inhibiting a protein-protein interaction mediated by an SH3 domain. The method includes the step of contacting the SH3 domain with a compound of Formula I, such that a protein-protein interaction mediated by an SH3 domain is inhibited. In preferred embodiments, R
1
is a tetrapeptide, more preferably Ac-Pro-Arg-Pro-Leu or Ac-Ala-Pro-Ala-Leu. In preferred embodiments, R
1
is an amino acyl residue selected from the group consisting of Boc-Leu and Boc-Val. In other embodiments, R
1
is an aminocarboxy moiety represented by the formula —C(O)NHR
7
, in which R
7
is an aryl moiety or a bulky alkyl group. In preferred embodiments, R
2
is a moiety represented by the formula —C(R
2a
)(R
2b
)C(O)R
5
. In preferred embodiments, R
2b
is hydrogen and R
2a
is a side-chain moiety of a naturally occurring amino acid. In preferred embodiments, R
5
is a tripeptide moiety selected from the group consisting of Lys-Pro-Pro-OH and Ala-Pro-Gly-OH.
In another aspect, the invention provide
Castelhano Arlindo L.
Witter David J.
Cooper & Dunham LLP
Lukton David
OSI Pharmaceuticals, Inc.
White John P.
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