US2020347110A1PendingUtilityA1
Composition and Methods for Stimulating Gastrointestinal Motility
Est. expirySep 29, 2025(expired)· nominal 20-yr term from priority
A61K 38/25C07K 14/5759C07K 14/4705A61K 38/2264A61P 1/00A61P 1/04A61P 1/14C07K 14/60A61P 1/10C07K 14/575A61K 38/00A61P 1/08A61P 43/00
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Claims
Abstract
The present invention relates to a method of treating a transient impairment of the motility of the gastrointestinal system resulting from postoperative ileus in a patient wherein said method includes the step of administering a therapeutically effective amount of a peptidyl analog of ghrelin to said patient.
Claims
exact text as granted — not AI-modified1 . A method of stimulating the motility of the gastrointestinal system in a patient, said method comprising administering a peptidyl analog of ghrelin, a prodrug thereof, or a pharmaceutically acceptable salt of said analog or said prodrug.
2 . The method of claim 1 , wherein said patient is experiencing postoperative ileus following gastrointestinal surgery.
3 . (canceled)
4 . The method of claim 3 wherein said peptidyl analog of ghrelin comprises the following formula (I):
(R 2 R 3 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 (I)
wherein:
A 1 is Gly, Aib, Ala, B-Ala, or Acc;
A 2 is Ser, Aib, Act, Ala, Acc, Abu, Ava, Thr, or Val;
A 3 is Ser, Ser(C(O)—R 4 ), Asp(O—R 8 ), Asp(NH—R 9 ), Cys(S—R 14 ), Dap(S(O) 2 —R 10 ) Dab(S(O) 2 —R 11 ), Glu(O—R 6 ), Glu(NH—R 7 ), Thr, Thr(C(O)—R 5 ), or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi, 3-Thi, Trp, or Tyr;
A 5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, or Val;
A 6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr, or Val;
A 7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 9 is His, Apc, Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 -)Phe or deleted;
A 10 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle, Tle, or deleted;
A 13 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 14 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 15 is Arg, hArg, Acc, Aib, Apc, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, or deleted;
A 19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 23 is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val, or deleted;
A 24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val, or deleted;
A 26 is Gln, Aib, Asn, Asp, Glu, or deleted;
A 27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 28 is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
R 1 is —OH, —NH 2 , —(C 1 -C 30 )alkoxy, or NH—X 6 —CH 2 —Z 0 , wherein X 6 is a (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, and Z 0 is —H, —OH, —CO 2 H or —C(O)—NH 2 ;
R 2 and R 3 each is, independently for each occurrence, H, (C 1 -C 20 )alkyl or (C 1 -C 20 )acyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 14 each is, independently for each occurrence, (C 1 -C 40 )alkyl, (C 2 -C 40 )alkenyl, substituted (C 1 -C 40 ) alkyl, substituted (C 2 -C 40 ) alkenyl, alkylaryl, substituted alklyaryl, aryl or substituted aryl;
R 12 and R 13 each is, independently for each occurrence, H, (C 1 -C 40 )alkyl, (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, or —C(NH)—NH 2 , wherein when R 12 is (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, or —C(NH)—NH 2 , then R 13 is H or (C 1 -C 40 )alkyl;
n is, independently for each occurrence, 1, 2, 3, 4 or 5;
X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 , or CN;
provided that the peptide contains at least one amino acid selected from the groups consisting of:
A 2 is Aib, Acc, or Act;
A 3 is Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), Glu(NH-Hexyl), or Cys(S-Decyl);
A 5 is Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, or Val;
A 6 is Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
A 7 is Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
A 8 is Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 9 is Aib, Acc, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 -)Phe; and
A 10 is Acc, Aib, Asn, Asp, or Glu;
and further provided that the peptide is not (Lys 8 )hGhrelin(1-8)-NH 2 or (Arg 8 )hGhrelin(1-8)-NH 2 ; or a pharmaceutically acceptable salt thereof.
5 . The method of claim 3 wherein said peptidyl ghrelin analog comprises the following formula (II):
R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2 (II)
wherein:
A 1 is Aib, Apc or Inp;
A 2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 4 is 2-Fua, Orn, 2-Pal, 3-Pal, 4-Pal, Pff, Phe, Pim, Taz, 2-Thi, 3-Thi, Thr(Bzl);
A 5 is Apc, Dab, Dap, Lys, Orn, or deleted;
R 1 is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and
R 2 is OH or NH 2 ;
provided that when A 5 is Dab, Dap, Lys, or Orn, then:
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Taz, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Orn, Thr(Bzl), or Pff;
when A 5 is deleted, then:
A 3 is D-Bip, D-Bpa, or D-Dip; or
A 4 is 2-Fua, Pff, Taz, or Thr(Bzl); or
A 1 is Apc when
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Orn, 2-Pal, 3-Pal or 4-Pal;
or a pharmaceutically acceptable salt thereof.
6 . A method of claim 3 wherein said peptidyl ghrelin analog comprises the following formula (III):
(R 2 R 3 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 (III)
wherein:
A 1 is Gly, Aib, Ala, B-Ala, Acc or Gly(myristyl);
A 2 is Ser, Aib, Ala, Acc, Abu, Act, Ava, Thr or Val;
A 3 is Ser, Ser(C(O)—R 4 ), Asp(O—R 8 ), Asp(NH—R 9 ), Cys(S—R 14 ), Dap(S(O) 2 —R 10 ) Dab(S(O) 2 —R 11 ), Glu(O—R 6 ), Glu(NH—R 7 ), Thr(C(O)—R 5 ) or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
A 5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
A 6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
A 7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
A 8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 9 is His, Apc, Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X 1 , X 2 , X 3 , X 4 , and X 5 -)Phe;
A 10 is Gln, Acc, Aib, Asn, Asp or Glu;
A 11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle, Tle or Cha;
A 13 is Gln, Acc, Aib, Asn, Asp or Glu;
A 14 is Gln, Acc, Aib, Asn, Asp or Glu;
A 15 is Arg, hArg, Acc, Aib, Apc, Dab, Dap, Lys, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ) HN CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ) or hCys(R 17 );
A 16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ) or deleted;
A 17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ) HN CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), Lys(biotinyl) or deleted;
A 18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O-R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 21 is Pro, Dhp, Dmt, Inc, 3-Hyp, 4-Hyp, Ktp, Oic, Pip, Thz, Tic or deleted;
A 22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 23 is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted;
A 24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
A 25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
A 26 is Gln, Aib, Asn, Asp, Glu or deleted;
A 27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 28 is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
R 1 is —OH, —NH 2 , —(C 1 -C 30 )alkoxy or NH—X 6 —CH 2 —Z 0 , wherein X 6 is a (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl and Z 0 is —H, —OH, —CO 2 H or —C(O)—NH 2 ;
R 2 and R 3 is, independently for each occurrence thereof, selected from the group consisting of H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 1 -C 30 )acyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted aryl(C 1 -C 30 )alkyl and substituted aryl(C 1 -C 30 )acyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is, independently for each occurrence thereof, selected from the group consisting of (C 1 -C 40 )alkyl, (C 2 -C 40 )alkenyl, substituted (C 1 -C 40 ) alkyl, substituted (C 2 -C 40 ) alkenyl, alkylaryl, substituted alklyaryl, aryl and substituted aryl;
R 12 and R 13 is, independently for each occurrence thereof, selected from the group consisting of H, (C 1 -C 40 )alkyl, (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, biotinyl and —C(NH)—NH 2 ,
X 1 , X 2 , X 3 , X 4 , and X 5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 and CN; and
n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
provided that:
(I). when R 2 is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 2 -C 30 )acyl, or substituted aryl(C 1 -C 30 )acyl, R 3 is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl or substituted aryl(C 1 -C 30 )alkyl;
(II). when R 12 is (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, biotinyl or —C(NH)—NH 2 , then R 13 is H or (C 1 -C 40 )alkyl;
(III). at least one of A 15 , A 16 , A 17 , A 18 , A 19 or A 20 must be selected from the group consisting of Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH 2 5 R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ) Cys(R 15 ), hCys(S—R 16 ) and hCys(R 17 ); and
(IV). when any of the group consisting of A 15 , A 16 , A 17 , A 19 and A 20 is HNCH((CH 2 ) n —N(R 12 R 13 ))—C(O), then R 12 must be biotinylated;
or a pharmaceutically acceptable salt thereof.
7 - 10 . (canceled)
11 . A method of treating opioid-related bowel dysfunction in a patent, said method comprising administering a peptidyl analog of ghrelin, a prodrug thereof, or a pharmaceutically acceptable salt of said analog or said prodrug.
12 . The method of claim 11 , wherein said peptidyl analog of ghrelin comprises the following formula (I):
(R 2 R 3 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 (I)
wherein:
A 1 is Gly, Aib, Ala, B-Ala, or Acc;
A 2 is Ser, Aib, Act, Ala, Acc, Abu, Ava, Thr, or Val;
A 3 is Ser, Ser(C(O)—R 4 ), Asp(O—R 8 ), Asp(NH—R 9 ), Cys(S—R 14 ), Dap(S(O) 2 —R 10 ) Dab(S(O) 2 —R 11 ), Glu(O—R 6 ), Glu(NH—R 7 ), Thr, Thr(C(O)—R 5 ), or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi, 3-Thi, Trp, or Tyr;
A 5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, or Val;
A 6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr, or Val;
A 7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 9 is His, Apc, Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 -)Phe or deleted;
A 10 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle, Tle, or deleted;
A 13 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 14 is Gln, Acc, Aib, Asn, Asp, Glu, or deleted;
A 15 is Arg, hArg, Acc, Aib, Apc, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, or deleted;
A 19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 23 is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val, or deleted;
A 24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
A 25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val, or deleted;
A 26 is Gln, Aib, Asn, Asp, Glu, or deleted;
A 27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic, or deleted;
A 28 is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), or deleted;
R 1 is —OH, —NH 2 , —(C 1 -C 30 )alkoxy, or NH—X 6 —CH 2 —Z 0 , wherein X 6 is a (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, and Z 0 is —H, —OH, —CO 2 H or —C(O)—NH 2 ;
R 2 and R 3 each is, independently for each occurrence, H, (C 1 -C 20 )alkyl or (C 1 -C 20 )acyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 14 each is, independently for each occurrence, (C 1 -C 40 )alkyl, (C 2 -C 40 )alkenyl, substituted (C 1 -C 40 ) alkyl, substituted (C 2 -C 40 ) alkenyl, alkylaryl, substituted alklyaryl, aryl or substituted aryl;
R 12 and R 13 each is, independently for each occurrence, H, (C 1 -C 40 )alkyl, (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, or —C(NH)—NH 2 , wherein when R 12 is (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, or —C(NH)—NH 2 , then R 13 is H or (C 1 -C 40 )alkyl;
n is, independently for each occurrence, 1, 2, 3, 4 or 5;
X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 , or CN;
provided that the peptide contains at least one amino acid selected from the groups consisting of:
A 2 is Aib, Acc, or Act;
A 3 is Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), Glu(NH-Hexyl), or Cys(S-Decyl);
A 5 is Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, or Val;
A 6 is Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
A 7 is Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
A 8 is Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 9 is Aib, Acc, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 -)Phe; and
A 10 is Acc, Aib, Asn, Asp, or Glu;
and further provided that the peptide is not (Lys 8 )hGhrelin(1-8)-NH 2 or (Arg 8 )hGhrelin(1-8)-NH 2 ; or a pharmaceutically acceptable salt thereof.
13 . The method of claim 11 wherein said peptidyl ghrelin analog comprises the following formula (II):
R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2 (II)
wherein:
A 1 is Aib, Apc or Inp;
A 2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 4 is 2-Fua, Orn, 2-Pal, 3-Pal, 4-Pal, Pff, Phe, Pim, Taz, 2-Thi, 3-Thi, Thr(Bzl);
A 5 is Apc, Dab, Dap, Lys, Orn, or deleted;
R 1 is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and
R 2 is OH or NH 2 ;
provided that when A 5 is Dab, Dap, Lys, or Orn, then:
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Taz, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Orn, Thr(Bzl), or Pff;
when A 5 is deleted, then:
A 3 is D-Bip, D-Bpa, or D-Dip; or
A 4 is 2-Fua, Pff, Taz, or Thr(Bzl); or
A 1 is Apc when
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Orn, 2-Pal, 3-Pal or 4-Pal;
or a pharmaceutically acceptable salt thereof.
14 . A method of claim 11 wherein said peptidyl ghrelin analog comprises the following formula (III):
formula (III):
(R 2 R 3 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 (III)
wherein:
A 1 is Gly, Aib, Ala, B-Ala, Acc or Gly(myristyl);
A 2 is Ser, Aib, Ala, Acc, Abu, Act, Ava, Thr or Val;
A 3 is Ser, Ser(C(O)—R 4 ), Asp(O—R 8 ), Asp(NH—R 9 ), Cys(S—R 14 ), Dap(S(O) 2 —R 10 ) Dab(S(O) 2 —R 11 ), Glu(O—R 6 ), Glu(NH—R 7 ), Thr(C(O)—R 5 ) or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
A 5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
A 6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
A 7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
A 8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 9 is His, Apc, Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X 1 , X 2 , X 3 , X 4 , and X 5 -)Phe;
A 10 is Gln, Acc, Aib, Asn, Asp or Glu;
A 11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle, Tle or Cha;
A 13 is Gln, Acc, Aib, Asn, Asp or Glu;
A 14 is Gln, Acc, Aib, Asn, Asp or Glu;
A 15 is Arg, hArg, Acc, Aib, Apc, Dab, Dap, Lys, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ) HN CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ) or hCys(R 17 );
A 16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ) or deleted;
A 17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ) HN CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), Lys(biotinyl) or deleted;
A 18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH—R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HNCH—((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ), Cys(R 15 ), hCys(S—R 16 ), hCys(R 17 ), or deleted;
A 21 is Pro, Dhp, Dmt, Inc, 3-Hyp, 4-Hyp, Ktp, Oic, Pip, Thz, Tic or deleted;
A 22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 23 is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted;
A 24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
A 25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
A 26 is Gln, Aib, Asn, Asp, Glu or deleted;
A 27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 28 is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
R 1 is —OH, —NH 2 , —(C 1 -C 30 )alkoxy or NH—X 6 —CH 2 —Z 0 , wherein X 6 is a (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl and Z 0 is —H, —OH, —CO 2 H or —C(O)—NH 2 ;
R 2 and R 3 is, independently for each occurrence thereof, selected from the group consisting of H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 1 -C 30 )acyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted aryl(C 1 -C 30 )alkyl and substituted aryl(C 1 -C 30 )acyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 14 , R 15 , R 16 and R 17 is, independently for each occurrence thereof, selected from the group consisting of (C 1 -C 40 )alkyl, (C 2 -C 40 )alkenyl, substituted (C 1 -C 40 ) alkyl, substituted (C 2 -C 40 ) alkenyl, alkylaryl, substituted alklyaryl, aryl and substituted aryl;
R 12 and R 13 is, independently for each occurrence thereof, selected from the group consisting of H, (C 1 -C 40 )alkyl, (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, biotinyl and —C(NH)—NH 2 ,
X 1 , X 2 , X 3 , X 4 , and X 5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 and CN; and
n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
provided that:
(I). when R2 is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 2 -C 30 )acyl, or substituted aryl(C 1 -C 30 )acyl, R 3 is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl or substituted aryl(C 1 -C 30 )alkyl;
(II). when R12 is (C 1 -C 40 )acyl, (C 1 -C 30 )alkylsulfonyl, biotinyl or —C(NH)—NH 2 , then R 13 is H or (C 1 -C 40 )alkyl;
(III). at least one of A 15 , A 16 , A 17 , A 18 , A 19 or A 20 must be selected from the group consisting of Ser(C(O)—R 4 ), Thr(C(O)—R 5 ), Glu(O—R 6 ), Glu(NH—R 7 ), Asp(O—R 8 ), Asp(NH 2 5 R 9 ), Dap(S(O) 2 —R 10 ), Dab(S(O) 2 —R 11 ), HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O), Cys(S—R 14 ) Cys(R 15 ), hCys(S—R 16 ) and hCys(R 17 ); and
(IV). when any of the group consisting of A 15 , A 16 , A 17 , A 19 and A 20 is HNCH((CH 2 ) n —N(R 12 R 13 ))—C(O), then R 12 must be biotinylated;
or a pharmaceutically acceptable salt thereof.
15 - 18 . (canceled)
19 . A method of claim 1 , wherein said patient is a human.
20 . A method of claim 1 , wherein said patient in need of gastrointestinal stimulation is experiencing gastroesophageal reflux disease, ileus, emesis, gastroparesis, IBS, constipation, or colonic pseudo-obstruction.
21 . A method according to claim 20 , wherein said patient is experiencing ileus, emesis or gastroparesis.
22 - 27 . (canceled)
28 . A method according to claim 21 , wherein said patient is experiencing emesis.
29 . A method according to claim 28 , wherein said patient is experiencing emesis associated with treatment with an anti-cancer chemotherapeutic agent, pregnancy, bulimia, or anorexia.
30 . A method according to claim 29 , wherein said emesis is associated with treatment with an anti-cancer chemotherapeutic agent.
31 - 33 . (canceled)
34 . A method according to claim 21 , wherein said patient is experiencing gastroparesis.
35 . A method according to claim 34 , wherein said gastroparesis is associated with diabetes.
36 - 37 . (canceled)Cited by (0)
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