US 2017/0008928 A1 · NOVEL PEPTIDES AND PEPTIDE DERIVATIVES AND USES THEREOF

Abstract

The invention relates to cholecystokinin (CCK) derivatives of the general formula I: P-L-X1-X2-X3-Gly-Trp-X6-DMeAsp-X8-NH2, wherein P is Chem. 1: HOOC—(CH2)x—CO—*, wherein x is an integer in the range of 12-18; L is absent, or L comprises at least one linker element selected from Chem. 2: *—NH—CH(COOH)—(CH2)2—CO—*, Chem. 3: *—NH—(CH2)2—[O—(CH2)2]k—O—[CH2]n—CO—* wherein k is an integer in the range of 1-11 and n is an integer in the range of 1-5, Chem. 4: *—NH—CH(CH2OH)—CO—*, Chem. 5: *—NH—CH2—CO—*, and/or Chem. 6: *—NH—CH[(CH2)4—NH2]—CO—*; X1 is absent, Asp, DAsp, bAsp, DbAsp, Glu, or DGlu; X2 is Phe(4-sulfomethyl) or sTyr; X3 is Nle, Leu, Ala, Ile, Lys, Arg, Pro, Met, Phe, Ser, His, or Val; X6 is Nle, Ile, Gln, Met, Met(O2), Leu, Val, Pro, Hpg, or Ala; X8 is Phe, MePhe, 1Nal, Me1Nal, 2Nal, Me2Nal, Trp, or MeTrp. The invention also relates to the corresponding CCK peptides, as well as to methods for preparing the peptides and the derivatives. The invention also relates to pharmaceutical compositions and uses of the derivatives, in particular for treatment of obesity and related health problems, where the compounds may be used either alone or in combination with other weight reducing agents and optionally in addition to diet and exercise. The derivatives have a high potency on the CCK-1 receptor (CCK-1R), a high selectivity for the CCK-1R as compared to the CCK-2R, effect on food intake in vivo, very long half-lives, and are chemically very stable.

Claims26

Dependent claims

A peptide derivative comprising the formula P-L-X1-X2-X3-Gly-Trp-X6-DMeAsp-X8-NH2,

wherein P is HOOC—(CH2)x—CO—*, wherein x is an integer in the range of 12-18;
wherein L is absent or comprises at least one linker element selected from the group consisting of
*—NH—CH(COOH)—(CH2)2—CO—*,
*—NH—(CH2)2—[O—(CH2)2]k—O—[CH2]n—CO—*,
*—NH—CH(CH2OH)—CO—*,
*—NH—CH2—CO—*,
and
*—NH—CH[(CH2)4—NH2]—CO—*,
wherein k is an integer in the range of 1-11, and wherein n is an integer in the range of 1-5;
wherein X1 is absent or is selected group from the group consisting of Asp, DAsp, bAsp, DbAsp, Glu, and DGlu;
wherein X2 is selected from the group consisting of Phe(4-sulfomethyl) and sTyr;
wherein X3 is selected from the group consisting of Nle, Leu, Ala, Ile, Lys, Arg, Pro, Met, Phe, Ser, His, and Val;
wherein X6 is selected from the group consisting of Nle, Ile, Gln, Met, Met(O2), Leu, Val, Pro, Hpg, and Ala;
wherein X8 is selected from the group consisting of Phe, MePhe, 1Nal, Me1Nal, 2Nal, Me2Nal, Trp, and MeTrp;
and
wherein the peptide derivative is C-terminally amidated by the NH2 group;
or a pharmaceutically acceptable salt, amide, or ester thereof.

14 more elements

A peptide comprising the amino acid sequence X1-X2-X3-Gly-Trp-X6-DMeAsp-X8-NH2,

wherein
X1 is absent or is selected from the group consisting of Asp, DAsp, bAsp, DbAsp, Glu, and DGlu;
X2 is selected from the group consisting of Phe(4-sulfomethyl) and sTyr;
X3 is selected from the group consisting of Nle, Leu, Ala, Ile, Lys, Arg, Pro, Met, Phe, Ser, His, and Val;
X6 is selected from the group consisting of Nle, Ile, Gln, Met, Met(O2), Leu, Val, Pro, Hpg, and Ala;
X8 is selected from the group consisting of Phe, MePhe, 1Nal, Me1Nal, 2Nal, Me2Nal, Trp, and MeTrp;
and
wherein the peptide is C-terminally amidated by the NH2 group;
or a pharmaceutically acceptable salt, amide, or ester thereof.

6 more elements

A method for treatment of overweight, comprising

administering a pharmaceutical composition comprising a peptide derivative and a pharmaceutically acceptable excipient to a subject in need thereof,
wherein the peptide derivative comprises the formula P-L-X1-X2-X3-Gly-Trp-X6-DMeAsp-X8-NH2,
wherein P is HOOC—(CH2)x—CO—*, wherein x is an integer in the range of 12-18;
wherein L is absent or comprises at least one linker element selected from the group consisting of
*—NH—CH(COOH)—(CH2)2—CO—*,
*—NH—(CH2)2—[O—(CH2)2]k—O—[CH2]n—CO—*,
*—NH—CH(CH2OH)—CO—*,
*—NH—CH2—CO—*,
and
*—NH—CH[(CH2)4—NH2]—CO—*,
wherein k is an integer in the range of 1-11, and wherein n is an integer in the range of 1-5;
wherein X1 is absent or is selected group from the group consisting of Asp, DAsp, bAsp, DbAsp, Glu, and DGlu;
wherein X2 is selected from the group consisting of Phe(4-sulfomethyl) and sTyr;
wherein X3 is selected from the group consisting of Nle, Leu, Ala, Ile, Lys, Arg, Pro, Met, Phe, Ser, His, and Val;
wherein X6 is selected from the group consisting of Nle, Ile, Gln, Met, Met(O2), Leu, Val, Pro, Hpg, and Ala;
wherein X8 is selected from the group consisting of Phe, MePhe, 1Nal, Me1Nal, 2Nal, Me2Nal, Trp, and MeTrp;
and
wherein the peptide derivative is C-terminally amidated by the NH2 group;
or a pharmaceutically acceptable salt, amide, or ester thereof.

16 more elements

Dependencies are inferred from the claim text.

Novel peptides and peptide derivatives and uses thereof

Life of this patent

Novel peptides and peptide derivatives and uses thereof

Life of this patent

Abstract

Claims26