Boronic ester and acid compounds, synthesis and uses

Details Boronic ester and acid compounds, synthesis and uses Boronic ester and acid compounds, synthesis and uses

2003-03-19

2004-06-08

Ramsuer, Robert W. (Department: 1626)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S013000, C548S405000, C549S213000

Reexamination Certificate

active

06747150

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to boronic ester and acid compounds, their synthesis and uses.
2. Description of Related Art
The synthesis of N-terminal peptidyl boronic ester and acid compounds, in general and of specific compounds, has been described previously (Shenvi et al. U.S. Pat. No. 4,499,082 issued Feb. 12, 1985; Shenvi et al. U.S. Pat. No. 4,537,773 issued Aug. 27, 1985; Siman et al. WO 91/13904 published Sep. 19, 1991; Kettner et al.,
J. Biol. Chem.
259(24): 15106-15114 (1984). These compounds have been shown to be inhibitors of certain proteolytic enzymes (Shenvi et al. U.S. Pat. No. 4,499,082 issued Feb. 12, 1985; Shenvi et al. U.S. Pat. No. 4,537,773; Siman et al. WO 91/13904 published Sep. 19, 1991; Kettner at al.,
J. Biol. Chem.
259(24):15106-15114 (1984). A class of N-terminal tri-peptide boronic ester and acid compounds has been shown to inhibit the growth of cancer cells (Kinder et al. U.S. Pat. No. 5,106,948 issued Apr. 21, 1992). A broad class of N-terminal tri-peptide boronic ester and acid compounds and analogs thereof has been shown to inhibit renin (Kleeman et al. U.S. Pat. No. 5,169,841 issued Dec. 8, 1992).
In the cell, there is a soluble proteolytic pathway that requires ATP and involves covalent conjugation of the cellular proteins with the small polypeptide ubiquitin (“Ub”) (Hershko et al.,
A. Rev. Biochem.
61:761-807 (1992); Rechsteiner et al.,
A. Rev. Cell. Biol.
3:1-30(1987)). Thereafter, the conjugated proteins are hydrolyzed by a 26S proteolytic complex containing a 20S degradative particle called the proteasome (Goldberg,
Eur. J. Biochem.
203:9-23 (1992); Goldberg et al.,
Nature
357:375-379 (1992)). This multicomponent system is known to catalyze the selective degradation of highly abnormal proteins and short-lived regulatory proteins.
The 20S proteasome is composed of about 15 distinct 20-30 kDa subunits. It contains three different peptidase activities that cleave specifically on the carboxyl side of the hydrophobic, basic, and acidic amino acids (Goldberg et al.,
Nature
357:375-379 (1992); Goldberg,
Eur. J. Biochem.
203:9-23 (1992); Orlowski,
Biochemistry
29:10289 (1990); Rivett et al.,
Archs. Biochem. Biophys.
218:1 (1989); Rivett et al.,
J. Biol. Chem.
264:12,215-12,219 (1989); Tanaka et al.,
New Biol.
4:1-11 (1992)). These peptidase activities are referred to as the chymotrypsin-like activity, the trypsin-like activity, and the peptidylglutamyl hydrolyzing activity, respectively.
Various inhibitors of the peptidase activities of the proteasome have been reported (Dick et al.,
Biochemistry
30:2725-2734 (1991); Goldberg et al.,
Nature
357:375-379 (1992); Goldberg,
Eur. J. Biochem.
203:9-23 (1992); Orlowski,
Biochemistry
29:10289 (1990); Rivett et al.,
Archs. Biochem. Biophys.
218:1 (1989); Rivett et al.,
J. Biol. Chem.
264:12,215-12,219(1989); Tanaka et al.,
New Biol.
4:1-11 (1992); Murakami et al.,
Proc. Natl. Acad. Sci. U.S.A.
83:7588-7592 (1986); Li et al.,
Biochemistry
30:9709-9715 (1991); Goldberg,
Eur. J. Biochem.
203:9-23 (1992); Aoyagi et al.,
Proteases and Biological Control
, Cold Spring Harbor Laboratory Press (1975), pp. 429-454.
Stein et al., U.S. patent application Ser. No. 08/212,909 filed Mar. 15, 1994, describe the use of peptide aldehydes to 1) reduce the rate of loss of muscle mass in an animal by contacting cells of the muscle with a peptide aldelyde proteasome inhibitor, 2) reduce the rate of intracellular protein breakdown in an animal by contacting cells of the animal with a peptide aldehyde proteasome inhibitor, and 3) reduce the rate of degradation of p53 protein in an animal by administering to the animal a peptide aldehyde proteasome inhibitor.
Palombella et al., PCT application serial number PCT/US95/03315, filed Mar. 17, 1995, describe the use of peptide aldehydes to reduce the cellular content and activity of NF-&kgr;B in an animal by contacting cells of the animal with a peptide aldehyde inhibitor of proteasome function or ubiquitin conjugation.
The transcription factor NF-&kgr;B and other members of the rel family of protein complexes play a central role in the regulation of a remarkably diverse set of genes involved in the immune and inflammatory responses (Grilli et al.,
International Review of Cytology
143:1-62 (1993)). NF-&kgr;B exists in an inactive form in the cytoplasm complexed with an inhibitor protein, I&kgr;B. In order for the NF-&kgr;B to become active and perform its function, it must enter the cell nucleus. It cannot do this, however, until the I&kgr;B portion of the complex is removed, a process referred to by those skilled in the art as the activation of, or processing of, NF-&kgr;B. In some diseases, the normal performance of its function by the NF-&kgr;B can be detrimental to the health of the patient. For example, NF-&kgr;B is essential for the expression of the human immunodeficiency virus (HIV). Accordingly, a process that would prevent the activation of the NF-&kgr;B in patients suffering from such diseases could be therapeutically beneficial.
Goldberg and Rock, WO 94/17816, filed Jan. 27, 1994, describe the use of proteasome inhibitors to inhibit MHC-I antigen presentation. The ubiquitination/proteolysis pathway is shown to be involved in the processing of internalized cellular or viral antigens into antigenic peptides that bind to MHC-I molecules on an antigen presenting cell. Accordingly, inhibitors of this pathway would be useful for the treatment of diseases that result from undesired response to antigen presentation, including autoimmune diseases and transplant rejection.
Cyclins are proteins that are involved in cell cycle control in eukaryotes. Cyclins presumably act by regulating the activity of protein kinases, and their programmed degradation at specific stages of the cell cycle is required for the transition from one stage to the next. Experiments utilizing modified ubiquitin (Glotzer et al.,
Nature
349:132-138 (1991); Hershko et al.,
J. Biol. Chem.
266:376 (1991)) have established that the ubiquitination/proteolysis pathway is involved in cyclin degradation. Accordingly, compounds that inhibit this pathway would cause cell cycle arrest and would be useful in the treatment of cancer, psoriasis, restenosis, and other cell proliferative diseases.
SUMMARY OF THE INVENTION
The present invention provides previously unknown peptidyl boronic acid ester and acid compounds. The present invention also provides methods of using amino acid or peptidyl boronic ester and acid compounds, in general, as inhibitors of proteasome function.
In a first embodiment, the present invention provides novel boronic acid and ester compounds having formula (1a) or (2a), as set forth below.
An additional aspect of the present invention is related to the discovery that amino acid and peptidyl boronic acids and esters, in general, are potent and highly selective proteasome inhibitors and can be employed to inhibit proteasome function. Inhibition of proteasome function has a number of practical therapeutic and prophylactic applications.
In a second embodiment, the present invention provides a method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a proteasome inhibitor having formula (1b) or (2b) as defined below. This aspect of the present invention finds practical utility in inhibiting (reducing or preventing) the accelerated breakdown of muscle proteins that accompanies various physiological and pathological states and is responsible to a large extent for the loss of muscle mass (atrophy) that follows nerve injury, fasting, fever, acidosis, and certain endocrinopathies.
In a third embodiment, the present invention provides a method for reducing the activity of NF-&kgr;B in a cell comprising contacting the cell with a proteasome inhibitor of the formula (1b) or (2b), as set forth below. The inhibitors employed in the practice of the present invention are capable of preventing this activation. Thus, blocking NF-&kgr;B activity is contemplated as posse

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