Src family SH2 domain inhibitors

Details Src family SH2 domain inhibitors Src family SH2 domain inhibitors

1999-11-12

2001-07-31

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S224000

Reexamination Certificate

active

06268365

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to compounds that bind to the Src family SH2 domains of particular regulatory proteins. Specifically, the compounds of this invention possess the ability to disrupt the interaction between regulatory proteins possessing one or more SH2 domains and their native ligands. Accordingly, the compounds of this invention are useful for the treatment and prevention of neoplastic and chronic inflammatory diseases. In one embodiment, this invention relates to a novel class of Src family SH2 inhibitors and pharmaceutical compositions comprising these compounds. This invention also relates to methods for producing these Src family S112 inhibitors. Because of their ability to target Src family SH2 domains, the compounds and pharmaceutical compositions of this invention are particularly well suited as agonists and antagonists of tyrosine-kinase dependent regulatory proteins containing Src family SH12 binding domains.
BACKGROUND OF THE INVENTION
The activation of cells by growth factors, mitogens and antigens resulting in proliferation and differentiation is often dependent on inducible tyrosine kinase activity. This tyrosinc kinase activity increases the phosphotyrosine content of many receptor-like and cytoplasmic regulatory proteins. Often, the physical association of such regulatory proteins is mediated through those phosphotyrosine residues. The interaction between a regulatory protein and a tyrosine kinase is often a critical step in initiating and modulating cellular signal transduction pathways.
The receptor-mediated activation of cells is often dependent on inducible tyrosine kinase activity. Activation of tyrosine kinase signal transduction pathways result in a transient increase in intracellular tyrosine phosphorylation on selective subsets of regulatory proteins. This tyrosine phosphorylation of proteins provides multiple means of regulation. For example, tyrosine phosphorylation may modulate the enzymatic activity of proteins, as in the case of p561ck (sometimes referred to herein as “Lck”), PLC&ggr;, and PI-3-kinase. In addition to enzyme regulation through covalent modification, one of the major roles for tyrosine phosphorylation is to create a binding site for Src homology 2 domains (“SH2 domains”). SH2 domains are homologous motifs of approximately 100 amino acids, which recognize and bind to the phosphorylated sequences present on regulatory proteins and growth factor receptors (D. Anderson et al.,
Science,
250, pp. 979-82 (1990)). A particularly important subset of proteins containing SH2 domains is the Src family of proteins (“Src family”).
One of the primary purposes of the Src family phosphoprotein/SH2 domain interaction is to initiate the association of proteins into an activation complex, often around the intracellular domain of the receptor itself. This role of the Src family SH2 domain mediates and organizes the ordered, physical assembly of the various proteins in the activation complex. The activity of a number of immunologically important Src family SH2 domain-containing proteins, including Src, Fyn, Fgr, Yes, I~yn, Hck and Lck, is mediated in this way. P56lck is of particular interest because it has been associated with the signal transduction cascade needed for T-cell activation mediated by the T-cell receptor (TCR) (D.B. Straus et al.,
Cell
70, pp. 585-93 (1992)).
Disrupting the interaction between Src family S132 domains and their phosphotyrosine-bearing native ligands (referred to herein as “Src family SI 12 domain inhibition”) represents a unique therapeutic approach to immunomodulation and the treatment or prevention of disorders associated with aberrant cellular transduction modulated by Src family SH2 domain binding interactions, such as certain autoimmune and inflammatory disorders, cancer and diabetes. However, despite considerable effort being devoted to this field of endeavor, no suitable drug candidates have yet emerged.
One major hurdle in this drug discovery effort has been the necessary inclusion of a phosphorylated tyrosine residue (sometimes abbreviated herein as “pTyr”), or a phosphorylated analog thereof, to perform the crucial role of the native phosphotyrosine in the phosphotyrosine-containing ligands of Src family SH2 domain-containing regulatory proteins. However, agents containing phosphotyrosine, other phosphorylated (X-amino acid residues, or phosphorylated analogs thereof, are not optimal therapeutic agents because the presence of the phosphorylated moiety substantially impedes their cell penetrability. In addition, the phosphate moiety tends to be metabolically unstable and therefore, results in premature degradation of the therapeutic agent . In contrast, the absence of a phosphate moiety is often associated with agents having poor binding affinity and lack of potency. Prior attempts at producing therapeutic agents containing phosphotyrosyl mimetics have met with only marginal success, including the attempted use of the conformationally constrained pTyr analogue, N(X-acetyl pTyr amide (T.R. Burke, Jr. et al.,
J. Med. Chem.,
38, pp. 1386-96 (1995)). Another attempt to produce an active compound containing a phosphotyrosyl mimetic replaced pTyr with (2-malonyl)Tyr (B. Ye et al.,
J. Med. Chem.,
38, pp. 4270-75 (1995)). The production of compounds containing other types of phosphate mimics include the use of NO
2
, CH
2
CONHOH, NH
2
, CH
2
COOH, CH
2
SO
3
H, CH
2
PO
3
H
2
, CHOHPO
3
H
2
, CF
2
PO
3
H, and OPSO
2
H
2
(T. Gilmer et al.,
J. Biol. Chem.
269(50), pp. 31711-19 (1994)), and CH
2
CH(COOH)
2
(Charifson et al.,
Biochemistry,
36, pp.6283-93 (1997)). However, until now, no effective replacement or mimic for the critical phosphotyrosine residue has been reported in connection with a Src family SH2 inhibitor so that cellular or in-vivo activity was clearly demonstrated. Recently published PCT patent application WO 97/12903 shows the only published example of which we are aware of cellular activity of any phosphate mimic. Specifically, WO 97/12903 refers to peptidomimetics incorporating CF
2
PO
3
H
2
and monoesters thereof (see Table 4 on page 112).
Another major hurdle to producing effective Src family SH2 domain inhibitors has been the high negative charge carried by native ligands of Src family SE12 domain binding proteins. For example, sequences containing pTyr-Glu-Glu-Ile have been reported as the optimal binding sequence for Src family S1l2 domains (Z. Songyang et al.,
Cell,
72, pp. 767-78 (1993)). Five negatively charged groups are associated with this sequence. The presence of these multiple negative charges, although useful for binding affinity, is not amenable for use in a bioavailable drug substance. As most of the above-referenced documents reveal, attempts to replace all of these negative charges with neutral- or positively charged-amino acids or amino acid mimics met with limited success due to reduced binding affinity (Gilmer, et al., supra, ).
A limited number of reports discuss the use of particular Src family SH2 domain inhibitors lo in whole cells. However, the majority of these trials have required the use of artificial means (e.g., extraneous agents or special microinjection techniques) to allow the Src family SH2 domain inhibitors to successfully enter the cell (Xiao, et al.,
J. Biol. Chem.
269, pp. 21244-8 (1994) and Wange, et al.,
J. Biol. Chem.
270, pp. 944-8 (1995)). To date, aside from WO 97/12903, no reported Src family SH2 inhibitor has been shown to possess high activity levels in whole cells without cell permeabilizers, signal peptides, prodrugs and the like.
Accordingly, the need exists for Src family SH2 inhibitors that overcome the above-mentioned deficiencies.
SUMMARY OF THE INVENTION
This invention satisfies the need for potent Src family SH2 inhibitors by providing a compound of formula (I):
wherein:
Ring a is selected from the group consisting of cycloalkyl, aryl or heterocyclyl;
A is selected from the group consisting of alkyl; alkenyl; alkynyl; alkoxy; cycloalkyl; cycloalkenyl; heterocyclyl and aryl; wherein said cyclo

Affiliated with

Also associated with

Rating

Src family SH2 domain inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Src family SH2 domain inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Src family SH2 domain inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2560825