Composition and Methods for Stimulating Gastrointestinal Motility

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.

1 - 37 . (canceled) 
     
     
         38 . A method of treating opioid-related bowel dysfunction in a patient, said method comprising administering to the patient a compound of 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, ß-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 (Are)hGhrelin(1-8)-NH 2 ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         39 . The method of  claim 38 , wherein:
 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.   
     
     
         40 . The method of  claim 38 , wherein the compound of formula (I) is selected from:
 (Dap 3 (octanesulfonyl))hGhrelin(1-28)-NH 2 ;   (Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2 ;   (A6c 5 )hGhrelin(1-28)-NH 2 ;   (Aib 2,6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , A5c 12 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , A5c 12 , Orn 15 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , A5c 12 , Apc 16 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Act 6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , 3-Pal 9 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Dmt 7 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2 ; and   (A5c 2 )hGhrelin(1-28)-NH 2 , or a pharmaceutically acceptable salt thereof.   
     
     
         41 . The method of  claim 38 , wherein the compound of formula (I) is selected from:
 (Act 2 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , A5c 5 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2 ;   (Aib 2,5 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , hLeu 5 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Cha 5 )hGhrelin(1-28)-NH 2 ;   (Aib 2,6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 ,Act 6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Thr 6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Abu 6 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , 4-Hyp 7 )hGkrelin(1-28)-NH 2 ;   (Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Pip 7 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Dhp 7 )hGhrelin(1-28)-NH 2 ;   (Aib 2 , Ktp 7 )hGhrelin(1-28)-NH 2 ;   (Aib 2,8 )hGhrelin(1-28)-NH 2 ; and   (Aib 2 , 2-Pal 9 )hGhrelin(1-28)-NH 2 , or a pharmaceutically acceptable salt thereof.   
     
     
         42 . The method of  claim 38 , wherein said patient is a human.