Caspase inhibitors and uses thereof

Details Caspase inhibitors and uses thereof Caspase inhibitors and uses thereof

2001-04-03

2003-10-14

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C560S041000

Reexamination Certificate

active

06632962

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the field of medicinal chemistry and relates to novel compounds, and pharmaceutical compositions thereof, that inhibit caspases that mediate cell apoptosis and inflammation. The invention also relates to methods of using the compounds and pharmaceutical compositions of this invention to treat diseases where caspase activity is implicated.
BACKGROUND OF THE INVENTION
Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, ischemic diseases and certain neurodegenerative disorders (see generally
Science,
1998, 281, 1283-1312; Ellis et al.,
Ann. Rev. Cell. Biol.,
1991, 7, 663).
Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly (Thornberry,
Chem. Biol.,
1998, 5, R97-R
103
). These signaling pathways vary depending on cell type and stimulus, but all apoptosis pathways appear to converge at a common effector pathway leading to proteolysis of key proteins. Caspases are involved in both the effector phase of the signaling pathway and further upstream at its initiation. The upstream caspases involved in initiation events become activated and in turn activate other caspases that are involved in the later phases of apoptosis.
Caspase-1, the first identified caspase, is also known as interleukin converting enzyme or “ICE.” Caspase-1 converts precursor interleukin-1&bgr; (“pIL-1&bgr;”) to the pro-inflammatory active form by specific cleavage of pIL-1&bgr; between Asp-116 and Ala-117. Besides caspase-1 there are also eleven other known human caspases, all of which cleave specifically at aspartyl residues. They are also observed to have stringent requirements for at least four amino acid residues on the N-terminal side of the cleavage site.
The caspases have been classified into three groups depending on the amino acid sequence that is preferred or primarily recognized. The group of caspases, which includes caspases 1, 4, and 5, has been shown to prefer hydrophobic aromatic amino acids at position 4 on the N-terminal side of the cleavage site. Another group which includes caspases 2, 3 and 7, recognize aspartyl residues at both positions 1 and 4 on the N-terminal side of the cleavage site, and preferably a sequence of Asp-Glu-X-Asp. A third group, which includes caspases 6, 8, 9 and 10, tolerate many amino acids in the primary recognition sequence, but seem to prefer residues with branched, aliphatic side chains such as valine and leucine at position 4.
The caspases have also been grouped according to their perceived function. The first subfamily consists of caspases-l (ICE), 4, and 5. These caspases have been shown to be involved in pro-inflammatory cytokine processing and therefore play an important role in inflammation. Caspase-1, the most studied enzyme of this class, activates the IL-1&bgr; precursor by proteolytic cleavage. This enzyme therefore plays a key role in the inflammatory response. Caspase-1 is also involved in the processing of interferon gamma inducing factor (IGIF or IL-18) which stimulates the production of interferon gamma, a key immunoregulator that modulates antigen presentation, T-cell activation and cell adhesion.
The remaining caspases make up the second and third subfamilies. These enzymes are of central importance in the intracellular signaling pathways leading to apoptosis. One subfamily consists of the enzymes involved in initiating events in the apoptotic pathway, including transduction of signals from the plasma membrane. Members of this subfamily include caspases-2, 8, 9 and 10. The other subfamily, consisting of the effector capsases 3, 6 and 7, are involved in the final downstream cleavage events that result in the systematic breakdown and death of the cell by apoptosis. Caspases involved in the upstream signal transduction activate the downstream caspases, which then disable DNA repair mechanisms, fragment DNA, dismantle the cell cytoskeleton and finally fragment the cell.
Knowledge of the four amino acid sequence primarily recognized by the caspases has been used to design caspase inhibitors. Reversible tetrapeptide inhibitors have been prepared having the structure CH
3
CO—[P4]—[P3]—[P2]—CH(R)CH
2
CO
2
H where P2 to P4 represent an optimal amino acid recognition sequence and R is an aldehyde, nitrile or ketone capable of binding to the caspase cysteine sulfhydryl. Rano and Thornberry,
Chem. Biol.
4, 149-155 (1997); Mjalli, et al.,
Bioorg. Med. Chem. Lett.
3, 2689-2692 (1993); Nicholson et al.,
Nature
376, 37-43 (1995). Irreversible inhibitors based on the analogous tetrapeptide recognition sequence have been prepared where R is an acyloxymethylketone —COCH
2
OCOR′. R′ is exemplified by an optionally substituted phenyl such as 2,6-dichlorobenzoyloxy and where R is COCH
2
X where X is a leaving group such as F or Cl. Thornberry et al.,
Biochemistry
33, 3934 (1994); Dolle et al.,
J Med. Chem.
37, 563-564 (1994).
The utility of caspase inhibitors to treat a variety of mammalian disease states associated with an increase in cellular apoptosis has been demonstrated using peptidic caspase inhibitors. For example, in rodent models, caspase inhibitors have been shown to reduce infarct size and inhibit cardiomyocyte apoptosis after myocardial infarction, to reduce lesion volume and neurological deficit resulting from stroke, to reduce post-traumatic apoptosis and neurological deficit in traumatic brain injury, to be effective in treating fulminant liver destruction, and to improve survival after endotoxic shock. Yaoita et al.,
Circulation,
97, 276 (1998); Endres et al.,
J Cerebral Blood Flow and Metabolism,
18, 238, (1998); Cheng et al.,
J. Clin. Invest.,
101, 1992 (1998); Yakovlev et al.,
J Neuroscience,
17, 7415 (1997); Rodriquez et al.,
J. Exp. Med.,
184, 2067 (1996); Grobmyer et al.,
Mol. Med.,
5, 585 (1999).
In general, the peptidic inhibitors described above are very potent against some of the caspase enzymes. However, this potency has not always been reflected in cellular models of apoptosis. In addition peptide inhibitors are typically characterized by undesirable pharmacological properties such as poor oral absorption, poor stability and rapid metabolism. Plattner and Norbeck, in
Drug Discovery Technologies
, Clark and Moos, Eds. (Ellis Horwood, Chichester, England, 1990).
Recognizing the need to improve the pharmacological properties of the peptidic caspase inhibitors, smaller peptide inhibitors have been prepared.
WO 99/18781 (Cytovia) describes dipeptide inhibitors of apoptotic cell death having the structure
where R
1
is an N-terminal protecting group; AA is a residue of any natural &agr;-amino acid, or &bgr;-amino acid; R
2
is H or CH
2
R
4
where R
4
is an electronegative leaving group, and R
3
is alkyl or H, provided that AA is not His, Tyr, Pro or Phe.
Nonpeptide inhibitors of caspase-1 have also been reported. U.S. Pat. No. 5,756,466 (Bemis et al.); Dolle et al.,
J. Med. Chem.
39, 2438 (1996); Dolle et al.,
J. Med. Chem.
40, 1941 (1997).
WO 98/16502 (Warner-Lambert) describes ICE (caspase-1) inhibitors having the structure
wherein R
1
is, inter alia, R
3
CO—, R
3
is, inter alia, C
1
-C
6
alkyl, aryl, heteroaryl, —(CHR)
n
-aryl, and —(CHR)
n
-heteroaryl, and R
2
is selected from various groups.
EP623592 (Sterling) describes ICE (caspase-1) inhibitors having the structure
wherein R1 includes aryl and heteroaryl; A is an amino acid; n is 0-4; m is 0 or 1; and R
2
is aryl.
WO 97/24339 (Ono) describes ICE (caspase-1) inhibitors having the structure
wherein R1 includes aryl and heteroaryl; AA1 and AA2 are single bonds or amino acid residues; Tet represents a tetrazole ring; Z represents alkylene, alkenylene, O, S etc; and E represents H, alkyl, etc.
While a number of caspase inhibitors have been repo

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