Compounds for reversing drug resistance

Details Compounds for reversing drug resistance Compounds for reversing drug resistance

C - Chemistry, Metallurgy

07

K

C07K 5/04 (2006.01) A61K 38/04 (2006.01) C07K 7/06 (2006.01)

Patent

CA 2189978

The invention features novel peptide derivatives called Reversins, and provides for their use in a method of reducing the activity of the multi-drug transporter protein MDR1 in order to overcome multidrug resistance in a mammal. The peptide derivatives are of the formula (I) X1n-X2-X3(X4)n-X5, wherein n is 0 or 1, and each n is the same or different; X1 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; X2 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(Bal); X3 is Asp, Asu, Lys, Glu, Trp, Thx, Cpa, Nal, Pen, Phg, Dbt, Glu(OtBu), tert.-Leu, Leu, Nle, Pro, Tyr, Phe, or Tyr(Bzl); X4 is BOC-Glu(OBzl), Glu(OBzl), Asu, OBzl, Bzl, BOC, BOC-Lys(BOC), Z-Glu(OtBu), Asp(OBzl), Asp(OBz)-OBzl, benzyloxycarbonyl, O-(cyclo-hexyl), fluorenylmethyl ester, Glu(OtBu), Glu(OtBu)-OBzl, 1-amino-adamantine, aminomethylcyclohexane, indoline, phenylethylamide, or dicyclohexylamide; and X5 is OMe, OBzl, OtBu, Phe-OMe, -O- (cyclohexyl), Trp-OMe, (chlorophenyl)-isobutylamide, fluorenylmethyl ester, ONp, 1-aminoadamantane, aminomethylcyclohexane, indoline, phenylethylamide, or dicyclohexylamide.

L'invention concerne de nouveaux dérivés de peptides appelés réversines, ainsi qu'un procédé de mise en application desdits dérivés visant à limiter l'activité d'une protéine de transport d'agents thérapeutiques médicamenteux multiples (MDR1), afin d'annihiler, chez un mammifère, la résistance auxdits agents. Ces dérivés sont représentés par la formule (I): X?1¿¿n?-X?2¿-X?3¿(X?4¿)¿n?-X?5¿ dans laquelle n est 0 ou 1, et chaque n est semblable ou différent; X?1¿ représente BOC, BOC-Asu, Z-Asu, benzyloxycarbonyle, Glu(OBzl)-OBzl, Trp-OMe, Trp-Phe-OMe, Phe-Trp-OMe, Phe-Phe-OtBu, Trp-Trp-OtBu, indoloacétyle, benzoyle, une alkylamine de 1-4 carbones, dibenzylamide, tryptamide, 1-amino-adamantine, aminométhylcyclohexane, indoline, phényléthylamide ou dicyclohexylamide; X?2¿ représente Glu(OBzl), Asp(OBzl), succinyle, O,O-dibenzoyltartaroyle, diphénoyle, muconyle, 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), ou Ser(Bal); X?3¿ représente Asp, Asu, Lys, Glu, Trp, Thx, Cpa, Nal, Pen, Phg, Dbt, Glu(OtBu), tert.-Leu, Leu, Nle, Pro, Tyr, Phe, ou Tyr(Bzl); X?4¿ représente BOC-Glu(OBzl), Glu(OBzl), Asu, OBzl, Bzl, BOC, BOC-Lys(BOC), Z-Glu(OtBu), Asp(OBzl), Asp(OBz)-OBzl, benzyloxycarbonyle, O-(cyclo-hexyle), fluorenylméthyl ester, Glu(OtBu), Glu(OtBu)-OBzl, 1-amino-adamantine, aminométhylcyclohexane, indoline, phényléthylamide, ou dicyclohexylamide; et X?5¿ représente OMe, OBzl, OtBu, Phe-OMe, -O-(cyclohexyle), Trp-OMe, (chlorophényle)-isobutylamide, fluorénylméthyl ester, ONp, 1-aminoadamantane, aminométhylcyclohexane, indoline, phényléthylamide ou dicyclohexylamide.

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