Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-02
2002-09-10
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S311000, C514S365000, C514S461000
Reexamination Certificate
active
06448245
ABSTRACT:
FIELD
This invention relates to enzymatic inhibitors, particularly calpain inhibitors, and more particularly, calpain inhibition by HIV protease inhibitors.
BACKGROUND
Calpains and Calpain Inhibitors
Calpains are mammalian calcium-dependent neutral cysteine proteases involved in programmed cell death (apoptosis). Calpains are referred to as cysteine proteases because they include a cysteine residue that plays a critical role in the catalytic process. In the presence of calcium, a cysteine protease catalytic triad forms when three amino acid residues (Cys 105, His262, and Asn 286) are brought together in the active site.
Two major classes of calpains are known, &mgr;-calpain and m-calpain, which differ in their sensitivities toward calcium. Some tissue-specific forms of calpain also have been identified. Substrates of calpain include cellular proteins such as cytoskeletal proteins, membrane-bound receptors, calmodulin binding proteins, myofibrillar proteins, enzymes, and transcription factors.
Calpain can become activated under ischemic conditions. It has been proposed that ischemia overactivates cellular membrane receptors, which causes an influx of calcium ions into the cell. This influx activates calcium-dependent enzymes, including calpains, and the calpains begin digesting cellular proteins, which contributes to cell death.
Inhibition of calpain has provided therapeutic possibilities for a number of different diseases, including cerebral ischemia (particularly strokes), traumatic brain injury, subarachnoid hemorrhage, chronic neurodegeneration (e.g., Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis), Alzheimer's disease, cardiac ischemia (particularly myocardial infarction), muscular dystrophy, cataracts, thrombotic platelet aggregation, restenosis, and joint inflammation (particularly arthritis).
A more detailed overview of calpains and calpain inhibitors can be found in Wang, et al.,
Advances in Pharmacology
, 37:117-52 (1997). Patents disclosing calpain inhibitors include: Zimmerman, et al., U.S. Pat. No. 5,374,623; Wang, et al., U.S. Pat. No. 5,760,048; Munoz, et al., U.S. Pat. No. 5,872,101; Munoz, et al., U.S. Pat. No. 5,969,100; and Spruce, et al., U.S. Pat. No. 6,004,933.
HIV Protease and Inhibitors
The human immunodeficiency virus (HIV) is a retrovirus that causes immunosuppression in humans and leads to a disease complex known as acquired immunodeficiency syndrome (AIDS). HIV protease is an aspartyl protease that plays a central role in viral processing by cleaving the HIV G
AG
and G
AG
-P
OL
polypeptides to produce mature viral core proteins and virus-specific enzymes. The HIV protease is called an aspartyl protease due to an important aspartyl residue in the active site that hydrolyzes the peptide bond of its substrate. Coffin et al.,
Retroviruses
(Cold Spring Harbor Laboratory Press, 1997), provides a more detailed explanation of HIV protease.
Commercially available HIV protease inhibitors include ritonavir, saquinavir, indinavir, nelfinavir, and amprenavir. Numerous other HIV protease inhibitors are currently being tested in humans, but have not yet been approved by the United States Food and Drug Administration (FDA) for use against HIV, including ABT378, BMS232632, DMP450, GW433908, L-756,423, and timpranavir. Other HIV protease inhibitors have been disclosed in the patent literature, including: Martin et al., U.S. Pat. No.5,196,438; Vacca et al., U.S. Pat. No. 5,413,999; Dressman et al., U.S. Pat. No. 5,484,926; Kempf et al., U.S. Pat. No. 5,541,206; WO 97/0139 and WO 00/04016 by Abbott Laboratories; and WO 98/56781 by Glaxo Group Limited.
SUMMARY
A variety of calpain inhibitors are disclosed, as well as methods of using these inhibitors to treat conditions associated with calpain activation. In some embodiments, HIV inhibitors are used to inhibit calpain activity. In other embodiments, the calpain inhibitor is an analog of or compound related to an HIV protease inhibitor.
A calpain may be inhibited by contacting the calpain with a disclosed inhibitor, such as an HIV protease inhibitor, analog, or related compound. In some embodiments, the calpain inhibitor is administered in therapeutically effective amounts to inhibit calpains within cells of subjects. In other embodiments, the calpain inhibitor is a compound having one or more of the following structures or clinical names, without reference to the ability of that compound to inhibit HIV protease activity:
(1) compounds of the formula,
wherein R
1
is monosubstituted thiazolyl, monosubstituted oxazolyl, monosubstituted isoxazolyl, or monosubstituted isothiazolyl; and wherein the substituent is selected from: lower alkyl; lower alkenyl; cycloalkyl; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; heterocyclic, wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl and wherein the heterocyclic is unsubstituted or substituted with a substituent selected from halo, lower alkyl, hydroxy, alkoxy, and thioalkoxy; (heterocyclic)alkyl, wherein the heterocyclic is defined as above; alkoxyalkyl; thioalkoxyalkyl; alkylamino; dialkylamino; phenyl, wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, lower alkyl, hydroxy, alkoxy and thioalkoxy; phenylalkyl, wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, lower alkyl, hydroxy, alkoxy and thioalkoxy; dialkylaminoalkyl; alkoxy; and thioalkoxy;
n is 1, 2 or 3;
R
2
is hydrogen or a lower alkyl;
R
3
is a lower alkyl;
R
4
and R
5
are independently selected from phenyl, thiazolyl, and oxazolyl, wherein the phenyl, thiazolyl or oxazolyl ring is unsubstituted or substituted with a substituent selected from halo, lower alkyl, hydroxy, alkoxy, and thioalkoxy;
R
6
is hydrogen or lower alkyl;
R
7
is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl, wherein the thiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted or substituted with lower alkyl;
X is hydrogen and Y is —OH, or X is —OH and Y is hydrogen, with the proviso that X is hydrogen and Y is —OH when Z is —N(R
8
)— and R
7
is unsubstituted, and with the proviso that X is hydrogen and Y is —OH when R
3
is methyl and R
7
is unsubstituted; and
Z is absent, —O—, —S—, —CH
2
— or —N(R
8
)— wherein R
8
is a lower alkyl, cycloalkyl, —OH or —NHR
9
, wherein R
9
is hydrogen, lower alkyl or an N-protecting group; or
(2) compounds of the formula,
wherein R is benzyloxycarbonyl or 2-quinolylcarbonyl; or,
(3) any of: ritonavir; saquinavir; indinavir; nelfinavir; or amprenavir.
Subjects at risk of suffering calpain-mediated physiological damage may be identified and administered an HIV protease inhibitor, or another compound disclosed herein, following an event associated with activation of calpain, such as ischemia in the cardiovascular (including the neurovascular) system, or the myocardial or neural tissues which these systems perfuse.
Some embodiments include treating or preventing calpain-mediated physiological damage in a subject. In these embodiments, calpain-mediated physiological damage is treated by administering to a subject a therapeutically effective amount of a pharmaceutical composition having at least one protease inhibitor. Particular examples of pharmaceutical compositions include those with plural HIV protease inhibitors; pharmaceutically compatible carriers, agents, counterions, adjuvants, or vehicles; and/or other calpain inhibitors (in addition to the compounds disclosed herein). Treatments may be prophylactic or reparative.
Particular examples of therapeutically effective amounts of compounds include amounts that provide an inhibition constant, K
i
, for inhibition of calpain less than or equal to about 11 &mgr;M. Additionally, therapeutically effective doses of compounds may be administered to a subject for a limited period of time, such as about a month, a week, or
DePetrillo Paolo B.
Wan Wenshuai
Henley III Raymond
Klarquist & Sparkman, LLP
The United States of America as represented by the Department of
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