Glycol and hydroxyphosphonate peptidomimetics as inhibitors...

Details Glycol and hydroxyphosphonate peptidomimetics as inhibitors... Glycol and hydroxyphosphonate peptidomimetics as inhibitors...

2000-06-20

2002-08-13

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S119000, C558S170000

Reexamination Certificate

active

06432933

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to analogs that display selective inhibitory activity against the aspartyl proteases, plasmepsin and cathepsin D.
BACKGROUND OF THE INVENTION
Resistance to known antimalarial therapies is becoming an increasing problem and new therapies are therefore desperately needed. Upon infecting a host, the malaria parasite avidly consumes the host hemoglobin as its source of nutrients. Plasmepsin I and II are proteases from
Plasmodium falciparum
that are necessary during the initial stages of hemoglobin hydrolysis and digestion, which occurs in the &agr;-chain, between Phe 33 and Leu 34, then other sites serve as substrates for hydrolysis as well. In culture, inhibition of plasmepsin by a peptidomimetic inhibitor is demonstrated as effective in preventing malarial hemoglobin degradation and in killing the parasite (Francis, S. E., Gluzman, I. Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M. L., Sherman, D. R., Russell, D. G., and Goldberg, D. E. (1994)
EMBO J,
13, 306-317). Thus, persons of skill in the art expect that plasmepsin inhibitors will provide effective antimalarial therapy in humans.
Cathepsin D is a human protease in the endosomal-lysosomal pathway, involved in lysosomal biogenesis and protein targeting, and may also be involved in antigen processing and presentation of peptide fragments. The protease therefore displays broad substrate specificity, but prefers hydrophobic residues on either side of the scissile bond.
Cathepsin D has been implicated in a variety of diseases, including connective tissue disease, muscular dystrophy, and breast cancer. Cathepsin D is also believed to be the protease which processes the &bgr;-amyloid precursor protein (Dreyer, R. N., Bausch, K. M., Fracasso, P., Hammond, L. J., Wunderlich, D., Wirak, D. O., Davis, G., Brini, C. M., Bucholz, T. M., Konig, G., Kamarck, M. E., and Tamburini, P. P. (1994)
Eur. J. Biochem.,
224, 265-271 and Ladror, U. S., Synder, S. W., Wang, G. T., Holzman, T. F., and Krafft, G. A. (1994)
J. Biol. Chem.,
269, 18422-18428), generating the major component of plaques in the brains of Alzheimer's patients. Consequently, persons of skill in the art expect that inhibitors of cathepsin D will be useful in treating Alzheimer's disease.
The present invention relates to peptidomimetic (hydroxystatine amides and hydroxyphosphonates) analogs and their inhibitory action against aspartyl proteases. More particularly, the invention relates to the identification of such compounds that display selective inhibitory activity against plasmepsin and cathepsin D. Although statine-containing peptides are known which inhibit aspartyl proteases (Shewale, J. G. ; Takahashi, R., Tang, J., Aspartic Proteinases and Their Inhibitors, Kostka, V., Ed. Walter de Gruyter: Berlin (1986) pp. 101-116; U.S. Ser. No. 08/743,944, filed Nov. 5, 1996 which is hereby incorporated by reference in its entirety), there are only a few selective inhibitors for cathepsin D (Lin, T. -Y.; Williams, H. R., Inhibition of Cathepsin D by Synthetic Oligopeptides,
J. Biol. Chem.
(1979), 254, 11875-11883; Rich, D. H.; Agarwal, N. S., Inhibition of Cathepsin D by Substrate Analogues Containing Statine and by Analogues of Pepstatin,
J. Med. Chem
. (1986) 29 (2519-2524)), and for plasmepsin (Silva, A. M. et al., Structure and Inhibition of Plasmepsin II, A Hemoglobin-Degrading Enzyme From Plasmodiumfalciparum,
Proceed Natl Acad Sci,
1996, 93, 10034-10039).
The present invention also relates to the solid phase synthesis of such peptidomimetic analogs.
SUMMARY OF THE INVENTION
I. Preferred Embodiments
The compounds of the present invention are represented by Formula I:
wherein:
R
1
is chosen from the group consisting of alkyl, —(CH
2
)
n
-cycloalkyl, —(CH
2
CH
2
)
n
NHC(O)-alkyl, and arylalkyl, wherein n=1-3;
R
2
is H or Ŝ —C(O)-L- wherein Ŝ is a solid support, and -L-, is a linker;
Y is —P(O)(OR
3
)
2
or —CH(OH)C(O)NR
4
R
5
, wherein R
3
is alkyl, arylalkyl, or haloalkyl; and R
4
and R
5
are independently chosen from the group consisting of H, alkyl, —(CH
2
)
n
-cycloalkyl, —(CH
2
CH
2
)
n
NHC(O)-alkyl, arylalkyl,
—C(H)(R
9
)CH
2
OR
10
, —C(H)(R
11
)C(H)(OR
10
)(R
11
),-alkyl-NHSO
2
R
11
, —C(H)(R
9
)C(O)NHR
10
, and —C(H)(R
9
)C(O)NHC(H)(R
9
)C(O)NHR
10
, wherein n=1-3;
R
9
is independently selected from the group consisting of alkyl and arylalkyl;
R
10
is independently selected from the group consisting of H, alkyl, and arylalkyl,
R
11
is independently selected from the group consisting of alkyl and aryl; or, when taken together, R
4
and R
5
can be
wherein
R
12
and R
13
are independently selected from the group consisting of H, halo, and alkoxy; and
Z is —C(O)R
6
and —C(O)C(H)(R
7
)OC(O)NHR
8
, wherein R
6
is alkyl, arylalkyl, aryl, —(CH
2
)
m
-cycloalkyl, heteroaryl, or
wherein m=0-3;
R
7
is H, alkyl, arylalkyl, or —(CH
2
)
n
-cycloalkyl; and
R
8
is alkyl, arylalkyl, or aryl.
Preferred compounds of Formula I are those wherein -L- is of Formula (a)
wherein the designated meta-position is attached to the —C(O)—and the ortho-methylene attaches to the amide nitrogen of Formula I.
A preferred embodiment of the invention are compounds of Formula I wherein:
Y is —P(O)(OR
3
)
2
, wherein R
3
is arylalkyl; and
Another preferred embodiment of the invention are compounds of Formula I wherein:
Y is —C(H)(OH)C(O)NHR
5
, wherein R
5
is
wherein R
9
is independently selected from the group consisting of alkyl and arylalkyl; and
wherein R
8
is alkyl or arylalkyl.
A further preferred embodiment of the invention are compounds of Formula I wherein:
Y is —C(H)(OH)C(O)NHR
5
, wherein R
5
is —C(H)(R
11
)C(H)(OR
10
)(R
11
), wherein
R
11
is aryl and R
10
is H, wherein each R
11
may be the same or different; and
wherein R
8
is alkyl or arylalkyl.
Yet another preferred embodiment of the invention are compounds of Formula I wherein:
Y is —C(H)(OH)C(O)NHR
5
, wherein R
5
is —C(H)(R
11
)C(H)(OR
10
)(R
11
), wherein
R
11
is aryl and R
10
is H, wherein each R
11
may be the same or different; and
Z is R
6
C(O)—, wherein R
6
is alkyl, arylalkyl, —(CH
2
)
m
-cycloalkyl, or
Another aspect of the invention is the use of divinylbenzene-cross-linked, polyethyleneglycol-grafted polystyrene beads optionally functionalized with amino groups (e.g., TentaGel™ S NH
2
, Rapp Polymere) as the solid supports for constructing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
II. Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:
Ac=Acetyl
BNB=4-bromomethyl-3-nitrobenzoic acid
BOC=t-butyloxycarbonyl
BSA=bovine serum albumin
Bu=butyl
c-=cyclo
DABCYL=4-(4-dimethylaminophenylazo)benzoic acid
DBU=Diazabicyclo[5.4.0]undec-7-ene
DCM=Dichloromethane=methylene chloride=CH
2
Cl
2
DIC=diisopropylcarbodiimide
DIEA=diisopropylethyl amine
DMAP=4-N,N-dimethylaminopyridine
DMF=N,N-dimethylformamide
DMSO=Dimethyl sulfoxide
DVB=1,4-divinylbenzene
EDANS=5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid
Et=ethyl
Fmoc=9-fluorenylmethoxycarbonyl
HOAc=acetic acid
HOBt=hydroxybenzotriazole
IBX=iodoxybenzoic acid
LiI=lithium iodide
m-=meta
Me=methyl
NMO=N-methylmorpholine oxide
o-=ortho
PEG=polyethylene glycol
Ph=phenyl
PfP=pentafluorophenol
r.t.=room temperature
sat'd=saturated
s-=secondary
t-=tertiary
TBS=tert-butyldimethylsilyl
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TMS=trimethylsilyl
Tris=tris(hydroxymethyl)aminomethane
UV=ultraviolet light
“Alkoxy” means alkoxy groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
“Alkyl” is intended

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