Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2001-08-10
2004-02-24
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C514S314000, C514S487000, C514S478000, C514S595000, C514S596000
Reexamination Certificate
active
06696488
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and compositions for inhibiting certain aspartyl proteases. More particularly it relates to methods and compounds for inhibiting the enzymatic activity of secretases involved in converting amyloid precursor protein to amyloid-&bgr; peptide. The methods and compounds of the invention can be used in the treatment of neurodegenerative disorders, notably Alzheimer's disease.
BACKGROUND OF THE INVENTION
Accumulating biochemical, histological, and genetic evidence supports the hypothesis that the 4 kDa &bgr;-amyloid protein (A&bgr;) is an essential component in the pathogenesis of Alzheimer's disease (AD). Selkoe D J, Science 275:630-631 (1997). Hardy
J, Proc Natl Acad Sci USA
94:2095-2097 (1997). Despite the intense interest in the role of A&bgr; in the etiology of AD, the molecular mechanism of A&bgr; biosynthesis is poorly understood. The 39-43-residue A&bgr; is formed via the sequential cleavage of the integral membrane amyloid precursor protein (APP) by &bgr;- and &ggr;-secretases. Selkoe D J,
Annu Rev Cell Biol
10:373-403 (1994). &bgr;-Secretase cleavage of APP occurs near the membrane, producing the soluble APP
8
-&bgr; and a 12 kDa C-terminal membrane-associated fragment (CTF). The latter is processed by &ggr;-secretase, which cleaves within the transmembrane domain of the substrate to generate A&bgr;. An alternative proteolytic event carried out by &agr;-secretase occurs within the A&bgr; portion of APP, releasing APP
8
-&agr;, and subsequent processing of the resulting membrane-bound 10 kDa CTF by &ggr;-secretase leads to the formation of a 3 kDa N-terminally truncated version of A&bgr; called p3.
Heterogeneous proteolysis of the 12 kDa CTF by &ggr;-secretase generates primarily two C-terminal variants of A&bgr;, 40- and 42-amino acid versions (A&bgr;
40
and A&bgr;
42
), and parallel processing of the 10 kDa CTF generates the corresponding C-terminal variants of p3. Although A&bgr;
42
represents only about 10% of secreted A&bgr;, this longer and more hydrophobic variant is disproportionally present in the amyloid plaques observed post mortem in AD patients (Roher A E et al.,
Proc Natl Acad Sci USA
90:10836-40 (1993); Iwatsubo T et al.,
Neuron
13:45-53 (1994)), consistent with in vitro studies illustrating the kinetic insolubility of A&bgr;
42
vis-á-vis A&bgr;
40
. Jarrett J T et al.,
Biochemistry
32:4693-4697 (1993). Importantly, all genetic mutations associated with early-onset (<60 years) familial Alzheimer's disease (FAD) result in increased A&bgr;
42
production. Selkoe D J,
Science
275:630-631 (1997); Hardy J,
Proc Natl Acad Sci USA
94:2095-2097 (1997). An understanding of the production of A&bgr; in general and that of A&bgr;
42
in particular is essential for elucidating the molecular mechanism of AD pathogenesis and may also lead to the development of new chemotherapeutic agents which strike at the etiological heart of the disease.
Both &ggr;-secretase and &bgr;-secretase are attractive targets for inhibitor design for the purpose of inhibiting production of A&bgr;. While &ggr;-secretase is an attractive target for inhibitor design, little is known about the structure, mechanism, or binding requirements of this unidentified protease.
In view of the foregoing, a need still exists to develop compositions and methods for treating disorders characterized by the production and deposition of &bgr;-amyloid.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds useful for inhibiting certain aspartyl proteases, particularly those involved in generating &bgr;-amyloid from APP. The compounds are useful for treating a subject having or at risk of having a &bgr;-amyloid-associated disease.
In a first aspect, the invention provides novel compounds of Formula I
wherein R
1
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aromatic, heteroaromatic, R
6
O(C═O), and R
7
R
8
N(C═O), wherein R
6
, R
7
, and R
8
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aromatic, and heteroaromatic, provided R
1
is not bonded to the Formula I nitrogen via a group
wherein Z is C and X is O, S, or N; R
2
and R
3
are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aromatic, and heteroaromatic; NH—R
4
is peptidyl or R
4
is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aromatic, and heteroaromatic; and non-hydrogen R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
can independently be substituted with alkylamino, alkoxy, amino, halide, nitro, sulfate, sulfonamide, sulfoxide, or thiol ether.
In some preferred embodiments R
1
is t-butyloxycarbonyl (Boc).
In these and other preferred embodiments R
2
is bulky and is selected from the group consisting of cyclohexyl, benzyl and other amino acid side chains. In a more preferred embodiment R
2
is benzyl, i.e., the side chain of phenylalanine.
In these and other preferred embodiments R
3
is selected from the group consisting of methyl, isopropyl, isobutyl, benzyl and other amino acid side chains. In a more preferred embodiment R
3
is benzyl, i.e., the side chain of phenylalanine. Also in these and other preferred embodiments R
3
is selected from the group consisting of the side chains of alanine, leucine, and valine.
In these and other preferred embodiments NH-R
4
is selected from the group consisting of alanine-phenylalanine O-methyl ester, leucine-alanine O-methyl ester, leucine—leucine O-methyl ester, leucine-phenylalanine O-methyl ester, leucine-valine O-methyl ester, and valine-phenylalanine O-methyl ester. In some preferred embodiments NH—R
4
is selected from the group consisting of leucine-valine-alanine O-methyl ester, leucine-valine-leucine O-methyl ester, leucine-valine-phenylalanine O-methyl ester, and leucine-valine—valine O-methyl ester.
In one particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is benzyl; and NH—R
4
is leucine—leucine O-methyl ester.
In another particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is isobutyl; and NH—R
4
is leucine—leucine O-methyl ester.
In another particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is benzyl; and NH—R
4
is alanine-phenylalanine O-methyl ester.
In another particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is benzyl; and NH—R
4
is leucine-valine O-methyl ester.
In another particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is benzyl; and NH—R
4
is valine-phenylalanine O-methyl ester.
In another particularly preferred embodiment R
1
is t-butyloxycarbonyl; R
2
is benzyl; R
3
is benzyl; and NH—R
4
is leucine-valine-phenylalanine O-methyl ester.
According to this aspect of the invention, certain embodiments embrace a stereoisomer of the compound of Formula I. Other related embodiments embrace a mixture of different stereoisomers of the compound of Formula I. In certain preferred embodiments all stereocenters are R.
Yet another embodiment is a pharmaceutically acceptable salt of the compound of Formula I.
Also provided according to this aspect of the invention is a pharmaceutical composition comprising a compound of Formula I and further comprising a pharmaceutically acceptable carrier. Preferably the pharmaceutically acceptable carrier is adapted for oral administration of a compound of Formula I to a subject. More preferably the pharmaceutically acceptable carrier is adapted for promoting delivery of a compound of Formula I to a brain of a subject.
The invention also provides a method for making a pharmaceutical composition. The method comprises placing a compound of Formula I according to this aspect of the invention in a pharmaceutically acceptable carrier. The method specifically embraces placing the above-identified preferred embodiments of the compound of Formula I in a pharmaceutically acceptable carrier.
In a second aspect the invention provides novel compounds of Formula I
Selkoe Dennis J.
Wolfe Michael S.
Kumar Shailendra
The Brigham and Women's Hospital Inc.
Wolf Greenfield and Sacks, P.C.
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