Compounds for reversing drug resistance

Details Compounds for reversing drug resistance Compounds for reversing drug resistance

1997-02-19

2001-10-02

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S019300, C530S330000, C530S331000

Reexamination Certificate

active

06297216

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to compounds for overcoming resistance that a patient may build to therapeutics.
Treatment of many diseases can be severely limited by resistance to the chosen therapeutic drug. For example, chemotherapy, while generally an effective treatment against human cancerous diseases, is hampered when a patient becomes resistant to the chemotherapeutic. In one special form of drug resistance, called “Multidrug Resistance,” the cell becomes resistant not only to the chemotherapeutic being administered, but to a wide range of structurally and functionally unrelated drugs simultaneously (see Ford et al.,
Pharmacological Reviews
, 42:155-199, 1992).
The cause of multidrug resistance is the appearance of an integral glycoprotein in the plasma membrane of the targeted cell, e.g., a tumor cell (FIG.
1
). The protein functions as a multidrug transporter, and is variously called MultiDrug-Resistance 1 protein (MDR1), P-glycoprotein (pleiotropic-glycoprotein), Pgp, or P-170. MDRl consists of 1280 amino acid residues, and contains 12 transmembrane segments and two nucleotide-binding domains. It strongly resembles prokaryotic and eukaryotic members of the so-called ABC (ATP Binding Cassette) transporters, or traffic ATPases (see Endicott et al.,
Annu. Rev. Biochem
. 58:137-171, 1989; Higgins,
Annu. Rev. Cell. Biol
. 8:67-113, 1992).
MDR1 naturally functions to, and is highly expressed in tissues normally responsible for, extruding toxic materials and waste-products from cells (e.g., lung, kidney, and liver), and secretes hydrophobic compounds from exocrine or endocrine glands (Gottesman et al.,
J. Biol. Chem
. 263:12163-12166, 1988; Higgins et al., supra). Consistent with its natural function, MDR1 catalyses an ATP-dependent extrusion of various cytotoxic drugs from the cell, e.g., vinca alkaloids, anthracyclines, and other natural antibiotics, thereby maintaining their cellular level at a subtoxic concentration. Thus, when expressed by tumor cells, MDR1 expels cytotoxic chemotherapeutic agents, and thus allows the tumor cell to survive anticancer treatments even at high drug doses. At the same time, “ordinary” cells, having no such extrusion mechanism, may receive a lethal drug exposure. Tumors developing from tissues normally expressing the MDR1 protein often show a primary drug resistance, while in other tumors a secondary drug resistance may develop after chemotherapy.
The phenomenon of multidrug resistance is not limited to tumor cells. MDR1 and its homologues are expressed in a wide variety of cell-types, including parasitic protozoa. Consequently, overexpression of a member of the MDR1 family of proteins creates obstacles to a wide variety of parasitic diseases, including malaria, African sleeping sickness, and others (Campbell et al.,
Chemotherapy of Parasitic Diseases
, Plenum Press:NY, 1986; Henderson et al.,
Mol. Cell. Biol
. 12:2855-65, 1992). MDR1 is also expressed by endothelial cells of human capillary blood vessels at the blood-brain barrier and blood-testis barrier (Ford et al. supra, at 159).
It is known that verapamil, a drug that blocks voltage-dependent calcium channels, stimulates the activity of MDR1-bound ATPase at a concentration of 1 to 20 &mgr;M but inhibits it as a concentration above 100 &mgr;M (Sarkadi et al.
J. Biol. Chem
. 267:4854-4858, 1992). While between these concentrations verapamil blocks the extrusion of antitumor drugs, its high toxicity severely limits its clinical use (Solary et al.
Leukemia
5:592-597, 1991; Dalton et al.
J. Clin. Oncology
7:415-418, 1989).
In SU-A-1544778, Golovina, T. N. et al describe the preparation of different peptides one of which, BOC-Leu-Tyr-OMe is structurally close to the peptides provided by the present invention. Nevertheless, no hints on the possible biological activity of said peptide are disclosed.
SUMMARY OF THE INVENTION
The invention generally features chemical compositions which reduce or overcome multidrug resistance in a mammal, e.g., a human, and in microorganisms causing disease in a mammal. The compounds, called “Formula (I)” compounds, or “Reversins”, are hydrophobic peptide derivatives which effectively compete with cytostatic drugs on the MDR1 protein, thus reducing or eliminating drug resistance.
“Multi-drug resistance”, as used herein, refers to the ability of cells to develop resistance to a broad range of structurally or functionally unrelated drugs. This occurs by outward transport of the drug from the cell, the transport being mediated by the MDR1 glycoprotein or its homologues. The term “multidrug resistance” also applies to the cross-resistance between drugs which is adversely affected by the Reversin compounds of the invention (see below). Preferably, “multidrug resistance” refers to the state which is dependent on expression or overexpression of the MDR1 protein or its homologues, and/or on gene amplification of human mdr1 or its homologues. Both primary and secondary multidrug resistance are included. Where the drug resistance is “primary” the cell has experienced no previous exposure to a member of the group of drugs, yet exhibits inherent resistance to them. Where drug resistance is “secondary”, the cell has been exposed to only one drug, or to only a subset of two or more, but not necessarily to the whole, group of drugs affected by cross-resistance.
The compounds of the invention, hereafter called “Reversins”, are of formula (I):
X
1
n
-X
2
-X
3
-(X
4
)
m
-X
5
  (I)
wherein
n and m are 0 to 1;
X
1
is BOC, BOC-Asu, Z-Asu, benzyloxycarbonyl, Glu(OBzl)-OBzl, Trp-OMe, Trp-Phe-OMe, Phe-Trp-OMe, Phe-Phe-OtBu, Trp-Trp-OtBu, indoloacetyl, benzoyl, an alkylamine of 1-4 carbons, dibenzylamide, tryptamide, 1-amino-adamantine, aminomethylcyclohexane, indoline, phenylethylamide or dicyclohexylamide;
X
2
is Glu(OBzl), Asp(OBzl), succinyl, O,O-dibenzoyltartaroyl, diphenoyl, muconyl, Thx, Cpa, Asu, Nal, Pen, Phg, Dbt, Lys(BOC), Lys(Z), Cys(Bzl), Thr(Bzl), Glu(OtBu), tert.-Leu, Leu, Nle, Pro, Phe, Tyr(Bzl), or Ser(Bzl);
X
3
is Asp, Asu, Lys, Glu, Trp, Thx, Cpa, Nal, Pen, Phg, Dbt, Glu(OtBu), tert.-Leu, Leu, Nle, Pro, Tyr, Phe; or Tyr(Bzl);
X
4
is BOC-Glu(OBzl), Glu(OBzl), Asu, OBzl, Bzl, BOC, BOC-Lys(BOC), Z-Glu(OtBu), Asp(OBzl), Asp(OBz)-OBzl, benzyl-oxycarbonyl, O-(cyclo-hexyl), fluorenylmethyl ester, Glu(OtBu), Glu(OtBu)-OBzl, 1-amino-adamantine, amino-methylcyclohexane, indoline, phenylethylamide, or dicyclohexylamide; and
X
5
is OMe, OBzl, OtBu, Phe-OMe, -O-(cyclohexyl), Trp-OMe, (chlorophenyl)-isobutylamide, fluorenylmethyl ester, ONp, 1-aminoadamantane, aminomethylcyclohexane, indoline, phenylethylamide, or dicyclohexylamide,
with the proviso that said formula (I) is not BOC-Leu-Tyr-OMe.
Formula (I) compounds containing amino acids with either the L or D configuration fall within the scope of the invention.
Side chain protecting groups of amino acids may be substituted by one or more halogen atoms, e.g., chloro-Z, or bromo-Z. Such blocking groups are known. A benzyl ester group can be substituted by one or more nitro groups in the second or fourth position of the benzene ring.
The abbreviations used herein are known to those skilled in the art (see, e.g.,
J. Biol. Chem
. 241:527, 1966
; J. Biol. Chem
. 247:977 1972; hereby incorporated by reference). Other abbreviations used herein are as follows:
AM:
acetoxymethyl ester
Asu:
aminosuccinic acid or aminosuccinoyl
BOC:
tert
.-butyloxycarbonyl,
Bzl:
benzyl,
Cpa:
4-chlorophenylalanyl,
Cys:
cysteinyl,
Dbt:
dibromotyrosyl,
DBTA:
dibenzoyltartaroyl,
DCC:
dicyclohexylcarbodiimide,
DCU:
dicyclohexylurea,
DIC:
diisopropylcarbodiimide,
DMF:
dimethylformamide
HPLC:
high pressure liquid chromatography,
MDR1:
product of multidrug resistance gene,
Me:
methyl,
Nal:
naphthylalanyl,
Nle:
norleucyl,
m.p.:
melting point,
OPFP:
pentailuorphenyl
ON
p
:
p-nitrophenyl
Pen:
penicillinalanyl,
Phe:
phenylalanyl,
Phg:
phenylglycyl,
Pro:
prolyl,
R
f
:
retention factor,
SUC:
succinyl,
TEA:
triethylamine,
THF:
tetrahydrofuran,
Thr:
threonyl,
Thx:
thyroxyl,
TLC:
thin layer chromatography,
Trp:
tryptophyl,
Z:

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