US2018009849A1PendingUtilityA1
Ghrelin analogues
Est. expiryFeb 3, 2032(~5.5 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 9/10A61P 9/12A61P 9/00A61P 5/00A61P 25/04A61P 3/04A61P 29/00A61P 3/00A61P 1/04A61P 11/00C07K 14/60A61K 38/00C07K 14/001A61P 25/00A61P 19/02A61P 19/10
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Claims
Abstract
The present invention relates, inter alia, to ghrelin analogues and their medical use, for example in the treatment of cachexia, chronic obstructive pulmonary disease, gastrointestinal disorders (e.g., gastroparesis and/or inflammatory disorders such as colitis, gut barrier dysfunction, and ischemia reperfusion injury), loss of body weight, and decreased appetite.
Claims
exact text as granted — not AI-modified1 . A compound having the formula I:
R 1 —Z—R 2 (I)
wherein R 1 is hydrogen, C 1-4 alkyl, formyl, acetyl, trifluoroacetyl or benzoyl; R 2 is OH or NH 2 ; and Z is an amino acid sequence having the formula Ia:
(Ia)
(SEQ ID NO: 2)
X 1 -X 2 -X 3 -Phe-Leu-Ser-Pro-X 8 -His-X 10 -X 11 -X 12 -X 13 -
X 14 -X 15 -X 16 -Glu-Ser-X 19 -X 20 -Pro-Pro-Ala-X 24 -Leu-
X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 1 is Pro;
X 2 is Ser; and
X 3 is selected among:
—NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—; (i)
—NH—CH(R 4 )—C(O)—; (ii)
—NH—CH[(CH 2 ) m —O—R 5 ]—C(O)—; and (iii)
—NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)—; (iv)
wherein
R 3 and R 4 are, independently, C 1-35 -alkyl or -alkenyl groups;
R 5 and R 6 are, independently, C 1-35 -acyl groups; and
n, m and p are integers 1, 2, 3, 4 or 5;
when present
X 8 is selected from Glu, Lys and Tyr;
X 10 is selected from Gln, Glu and Ser;
X 11 is selected from Arg, Lys and Ser;
X 12 is selected from Val, Ala, Pro, Lys, Thr and Leu;
X 13 is selected from Gln and Ser;
X 14 is selected from Gln, Lys, Tyr and Ser, or is absent;
X 15 is selected from Arg and Ser;
X 16 is selected from Lys, Ser and Pro;
X 19 is selected from Lys and Ser;
X 20 is selected from Lys, Glu and Ser;
X 24 is selected from Lys, Tyr and Ser;
X 26 is selected from Gln and Ser; and
X 28 is selected from Arg and Ser;
and one or more of said amino acid residues X 8 , X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 20 , X 24 , X 26 and X 28 , independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2- , wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue;
or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 comprising the formula I:
R 1 —Z—R 2 (I)
wherein
R 1 is hydrogen, C 1-4 alkyl, formyl, acetyl, trifluoroacetyl or benzoyl;
R 2 is —OH or —NH 2 ; and
Z is an amino acid sequence having the formula Ia:
(Ib)
(SEQ ID NO: 3)
X 1 -X 2 -X 3 -Phe-Leu-Ser-Pro-Glu-His-X 10 -X 11 -X 12 -X 13 -
X 14 -Arg-X 16 -Glu-Ser-X 19 -X 20 -Pro-Pro-Ala-X 24 -Leu-
X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 1 is Pro;
X 2 is Ser; and
X 3 is selected among:
—NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—; (i)
—NH—CH(R 4 )—C(O)—; (ii)
—NH—CH[(CH 2 ) m —O—R 5 ]—C(O)—; and (iii)
—NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)—; (iv)
wherein
R 3 and R 4 are, independently, C 1-35 -alkyl or -alkenyl groups;
R 5 and R 6 are, independently, C 1-35 -acyl groups; and
n, m and p are integers 1, 2, 3, 4 or 5;
when present
X 10 is selected from Gln and Ser;
X 11 is selected from Arg and Lys;
X 12 is selected from Val, Ala, Thr and Leu;
X 13 is selected from Gln and Ser;
X 14 is selected from Gln and Ser, or is absent;
X 16 is Lys;
X 19 is Lys;
X 20 is Lys;
X 24 is Lys; and
X 26 is selected from Gln and Ser;
X 28 is Arg;
and one or more of said amino acid residues X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 20 , X 24 , X 26 and X 28 , independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2 —, wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue;
or a pharmaceutically acceptable salt thereof.
3 . A compound according to claim 2 comprising the formula I:
R 1 —Z—R 2 (I)
wherein
R 1 is hydrogen, C 1-4 alkyl, formyl, acetyl, trifluoroacetyl or benzoyl;
R 2 is —OH or —NH 2 ; and
Z is an amino acid sequence having the formula Ia:
(Ib)
(SEQ ID NO: 3)
X 1 -X 2 -X 3 -Phe-Leu-Ser-Pro-Glu-His-X 10 -X 11 -X 12 -X 13 -
X 14 -Arg-X 16 -Glu-Ser-X 19 -X 20 -Pro-Pro-Ala-X 24 -Leu-
X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 1 is Pro;
X 2 is Ser; and
X 3 is selected among:
—NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—; (i)
—NH—CH(R 4 )—C(O)—; (ii)
—NH—CH[(CH 2 ) m —O—R 5 ]—C(O)—; and (iii)
—NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)—; (iv)
wherein
R 3 and R 4 are C 1-35 -alkyl or -alkenyl groups;
R 5 and R 6 are C 1-35 -acyl groups; and
n, m and p are integers 1, 2, 3, 4 or 5;
when present
X 10 is Gln;
X 11 is selected from Arg and Lys;
X 12 is selected from Val, Ala, Thr and Leu;
X 13 is Gln;
X 14 is Gln or is absent;
X 16 is Lys;
X 19 is Lys;
X 20 is Lys;
X 24 is Lys; and
X 26 is Gln;
X 28 is Arg;
and one or more of said amino acid residues X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 20 , X 24 and X 26 , independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2 —, wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue;
or a pharmaceutically acceptable salt thereof.
4 .- 8 . (canceled)
9 . A compound according to claim 1 wherein
Z is an amino acid sequence having the formula Ic:
(Ic)
(SEQ ID NO: 4)
Pro-Ser-X 3 -Phe-Leu-Ser-Pro-Glu-His-X 10 -X 11 -X 12 -
X 13 -X 14 -Arg-X 16 -Glu-Ser-X 19 -X 20 -Pro-Pro-Ala-X 24 -
Leu-X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 3 is selected from among:
—NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—; and (i)
—NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)—; (iv)
wherein
R 3 is a C 1-35 -alkyl or -alkenyl group;
R 6 is a C 1-35 -acyl group; and
n and p are integers 1, 2, 3, 4 or 5;
when present
X 10 is selected from Gln and Ser;
X 11 is selected from Arg and Lys;
X 12 is selected from Val, Ala, Thr and Leu;
X 13 is selected from Gln and Ser;
X 14 is selected from Gln and Ser, or is absent;
X 16 is Lys;
X 19 is Lys;
X 20 is Lys;
X 24 is Lys; and
X 26 is selected from Gln and Ser;
X 28 is Arg;
and wherein one or more of said amino acid residues X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 20 , X 24 , X 26 and X 28 independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2 —, wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue or a pharmaceutically acceptable salt thereof.
10 . A compound according to claim 1 wherein
Z is an amino acid sequence having the formula Id:
(Id)
(SEQ ID NO: 5)
Pro-Ser-X 3 -Phe-Leu-Ser-Pro-Glu-His-X 10 -X 11 -Val-
X 13 -X 14 -Arg-X 16 -Glu-Ser-X 19 -Ser-Pro-Pro-Ala-X 24 -
Leu-X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 3 is —NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—
wherein
R 3 is a C 1-35 -alkyl or -alkenyl group and n is an integer 1, 2, 3, 4 or 5;
when present
X 10 is selected from Gln and Ser;
X 11 is selected from Arg and Lys;
X 13 is selected from Gln and Ser;
X 14 is selected from Gln and Ser, or is absent;
X 16 is Lys;
X 19 is Lys;
X 24 is Lys; and
X 26 is selected from Gln and Ser;
X 28 is Arg;
and wherein one or more of said amino acid residues X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 24 , X 26 and X 28 independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2 —, wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue or a pharmaceutically acceptable salt thereof.
11 . A compound according to claim 1 wherein
Z is an amino acid sequence having the formula Id:
(Id)
(SEQ ID NO: 5)
Pro-Ser-X 3 -Phe-Leu-Ser-Pro-Glu-His-X 10 -X 11 -Val-
X 13 -X 14 -Arg-X 16 -Glu-Ser-X 19 -Ser-Pro-Pro-Ala-X 24 -
Leu-X 26 -Pro-X 28
or is a truncated form thereof lacking from 1 to 23 amino acids from the C-terminus;
wherein
X 3 —NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)—
wherein
R 6 is a C 1-35 -acyl group and p is an integer 1, 2, 3, 4 or 5;
when present
X 10 is selected from Gln, Glu and Ser;
X 11 is selected from Arg and Lys;
X 13 is selected from Gln and Ser;
X 14 is selected from Gln and Ser, or is absent;
X 16 is Lys;
X 19 is Lys;
X 24 is Lys; and
X 26 is selected from Gln and Ser;
X 28 is Arg;
and wherein one or more of said amino acid residues X 10 , X 11 , X 13 , X 14 , X 16 , X 19 , X 24 , X 26 and X 28 independently, is replaced with a modified lysine residue comprising a lipophilic substituent having the formula Z 1 Z 2 —, wherein Z 2 is a spacer moiety or is absent, and Z 1 is a lipophilic moiety conjugated, either via Z 2 or directly, to the side-chain of said lysine residue or a pharmaceutically acceptable salt thereof.
12 .- 15 . (canceled)
16 . A compound according to claim 1 , wherein X 3 is selected among:
—NH—CH[(CH 2 ) n —O—R 3 ]—C(O)—; and (i)
—NH—CH(R 4 )—C(O)— (ii)
or a pharmaceutically acceptable salt thereof.
17 . A compound according to claim 1 , wherein X 3 is selected among:
—NH—CH[(CH 2 ) m —O—R 5 ]—C(O)—; and (iii)
—NH—CH[(CH 2 ) p —NH—R 6 ]—C(O)— (iv)
or a pharmaceutically acceptable salt thereof.
18 . A compound claim 9 , wherein R 3 is a C 5-16 -alkyl or -alkenyl group or a pharmaceutically acceptable salt thereof.
19 . A compound according to claim 1 , wherein R 4 is a C 7-18 -alkyl or -alkenyl group or a pharmaceutically acceptable salt thereof.
20 . A compound according to claim 1 , wherein R 5 is a C 5-16 -acyl group or a pharmaceutically acceptable salt thereof.
21 . A compound according to claim 1 , wherein R 6 is a C 5-16 -acyl group or a pharmaceutically acceptable salt thereof.
22 . A compound according to claim 1 , wherein n, m or p is 1 or a pharmaceutically acceptable salt thereof.
23 . A compound according to claim 1 , wherein Z 1 is selected from dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl and eicosanoyl or a pharmaceutically acceptable salt thereof.
24 . A compound according to claim 1 , wherein Z 2 is a spacer moiety comprising one or more amino acid residues or a pharmaceutically acceptable salt thereof.
25 . A compound according to claim 1 , wherein Z 2 is an amino acid residue selected from Glu, γGlu and Bal, or a residue of an amino acid selected from 3-aminopropanoic acid, 4-aminobutanoic acid, 8-aminooctanoic acid and 8-amino-3,6-dioxaoctanoic acid or a pharmaceutically acceptable salt thereof.
26 . A compound according to claim 1 , wherein at least positions X 1 to X 13 and X 15 to X 28 of Z are present or a pharmaceutically acceptable salt thereof.
27 . A compound according to claim 1 , wherein position X 14 is present or a pharmaceutically acceptable salt thereof.
28 . A compound according to claim 1 , wherein position X 14 is absent.
29 . A compound according to claim 1 having the formula:
(SEQ ID NO: 18)
H-PS-S(O-octyl)-FLSPEHQRVQQRKES-K(hexadecanoyl)-
KPPAKLQPR-OH;
or a pharmaceutically acceptable salt thereof.
30 . (canceled)
31 . A compound according to claim 1 comprising an intramolecular bridge between a Lys residue and a Glu residue.
32 . A compound according to claim 1 which has at least one biological activity of native human ghrelin.
33 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
34 .- 36 . (canceled)
37 . A method for:
(i) treating cachexia, low body weight, loss of body weight, low or decreased appetite, low muscle mass, effects of gastrectomy or vagectomy, gut barrier dysfunction, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, or ischemia reperfusion injury; (ii) increasing food intake and/or body weight; (iii) inducing the production of growth hormone; or (iv) inducing increased motility of the gastrointestinal tract;
the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound claim 1 or a pharmaceutically acceptable salt thereof.
38 .- 44 . (canceled)Join the waitlist — get patent alerts
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