Analogues of glucose-dependent insulinotropic polypeptide (gip) modified at n-terminal

Abstract

There is provided a novel series of analogues of glucose-dependent insulinotropic polypeptide, pharmaceutical compositions containing said compounds, and the use of said compounds as GIP-receptor agonists or antagonists for treatment of GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.

What is claimed is: 
     
         1 . 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 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -A 39 -A 40 -A 41 -A 42 -A 43 -R 1 ,  (I)
   
       wherein:
 A 1  is Cpa, His, 4Hppa, 2-Pal, 3-Pal, 4-Pal, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, Taz, 3Thi, 7HO-Tic, Tyr(Ac), Tyr(Me), β-Tyr, 3Br-Tyr, 3,5Br-Tyr, 3Cl-Tyr, 2F-Tyr, 3F-Tyr, hTyr, 3I-Tyr, 3,5I-Tyr, αMe-Tyr, 2,6Me-Tyr, 3MeO-Tyr, 3NH 2 -Tyr, 3NO 2 -Tyr, 3OH-Tyr, or 3(HO—(CH 2 )Tyr; 
 A 2  is Ala, Abu, D-Abu, Acc, Aib, β-Ala, D-Ala, Gaba, Gly, Ser, D-Ser, Thr, D-Thr, Val, or D-Val; 
 A 3  is Glu, Aib, Asp, N-Me-Asp, Dhp, Dmt, N-Me-Glu, 3Hyp, 4Hyp, 4Ktp, Pro, hPro, Thz, or Tic; 
 A 4  is Gly, Acc, Aib, or β-Ala; 
 A 5  is Thr, Acc, Aib, or Ser; 
 A 6  is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, or Trp; 
 A 7  is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; 
 A 8  is Ser, Aib, or Thr; 
 A 9  is Asp, Aib, or Glu; 
 A 10  is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe; 
 A 11  is Ser, Acc, Aib, Nle, or Thr; 
 A 12  is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; 
 A 13  is Ala, Acc, Aib, β-Ala, D-Ala, Gly, or Ser; 
 A 14  is Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, or Val; 
 A 15  is Asp, Aib, or Glu; 
 A 16  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ); 
 A 17  is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; 
 A 18  is His, Amp, Arg, 2-Pal, 3-Pal, 4-Pal, Phe, or Tyr; 
 A 19  is Gln, Aib, or Asn; 
 A 20  is Gln, Aib, or Asn; 
 A 21  is Asp, Aib, or Glu; 
 A 22  is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, or Trp; 
 A 23  is Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle; 
 A 24  is Asn, Aib, or Gln; 
 A 25  is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe; 
 A 26  is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, or Tle; 
 A 27  is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, or Tle; 
 A 28  is Ala, Acc, or Aib; 
 A 29  is Gln, Aib, Asn, or deleted; 
 A 30  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 31  is Gly, Aib, Acc, β-Ala, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 32  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 33  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 34  is Asn, Aib, Gln, Ser, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 35  is Asp, Aib, Glu, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 36  is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, (X 4 ,X 5 ,X 6 ,X 7 ,X 8 )Phe, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 37  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 38  is His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 39  is Asn, Aib, Gln, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 40  is Ile, Acc, Aib, Ser, Thr, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 41  is Thr, Acc, Aib, Asn, Gln, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 42  is Gln, Acc, Aib, Asn, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 43  is Acc, Ado, Aib, Ala, Asn, Asp, His, Gln, Phe, Thr, Trp, HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ) y —CH 3 ), Cys(succinimide-N—(CH 2 ) s —NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ) s NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ) s NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 R 1  is OH, NH 2 , (C 1 -C 30 )alkoxy, or NH—X 2 —CH 2 —Z 0 , wherein X 2  is a (C 0 -C 30 ) hydrocarbon moiety and Z 0  is H, OH, CO 2 H, or CONH 2 ; 
 each of R 2 , R 3 , R 4  and R 5  is independently 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 1 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl, substituted aryl(C 1 -C 30 )alkyl, and substituted aryl(C 1 -C 30 )acyl; provided that when R 2  is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )acyl, or substituted aryl(C 1 -C 30 )acyl, then R 3  is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl, or substituted aryl(C 1 -C 30 )alkyl; further provided that when R 4  is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )acyl, or substituted aryl(C 1 -C 30 )acyl, then R 5  is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl, or substituted aryl(C 1 -C 30 )alkyl; 
 n is, independently for each occurrence, an integer from 1 to 5 inclusive; 
 s, t, x and y each is, independently for each occurrence, an integer from 1 to 30 inclusive; 
 X 4 , X 5 , X 6 , X 7  and X 8  each is, independently for each occurrence, H, F, CF 3 , Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , —CH 2 NH 2 , NO 2 , or CN; 
 provided that when A 1  is 4Hppa, then R 2  and R 3  are deleted; 
 further provided that the compound contains more than one amino acid substitutions or modifications at positions 1, 2 and 3; and 
 further provided that if the amino acid at position 1 is modified, it is not modified by: 
 (a) N-terminal alkylation; 
 (b) N-terminal acetylation; 
 (c) N-terminal acylation; 
 (d) the addition of an N-terminal isopropyl group; or 
 (e) the addition of an N-terminal pyroglutamic acid; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein:
 A 1  is Cpa, His, 4Hppa, 2Pal, 3Pal, 4Pal, 3Br-Phe, 4CF 3 -Phe, 3Cl-Phe, 4CN-Phe, 3F-Phe, 4F-Phe, 3,4F-Phe, 3,5F-Phe, 3,4,5F-Phe, 4Me-Phe, 4NH 2 -Phe, 4NH 2 CH 2 -Phe, 3OH-Phe, Taz, 3Thi, 7HO-Tic, Tyr(Ac), Tyr(Me), β-Tyr, 3Br-Tyr, 3,5Br-Tyr, 3Cl-Tyr, 2F-Tyr, 3F-Tyr, hTyr, 3I-Tyr, 3,5I-Tyr, αMe-Tyr, 2,6Me-Tyr, 3MeO-Tyr, 3NH 2 -Tyr, 3NO 2 -Tyr, 3OH-Tyr, or 3(HO—(CH 2 )Tyr;   A 2  is Ala, Aib, Gly;   A 3  is Glu, 4Hyp, or hPro;   A 4  is Gly;   A 5  is Thr;   A 6  is Phe;   A 7  is Ile, A5c, or A6c;   A 8  is Ser;   A 9  is Asp;   A 10  is Tyr;   A 11  is Ser, A5c, or Aib;   A 12  is Ile;   A 13  is Ala or Aib;   A 14  is Met, A5c, or Nle;   A 15  is Asp;   A 16  is Lys;   A 17  is Ile;   A 18  is His;   A 19  is Gln;   A 20  is Gln;   A 21  is Asp;   A 22  is Phe;   A 23  is Val;   A 24  is Asn;   A 25  is Trp;   A 26  is Leu;   A 27  is Leu;   A 28  is Ala;   A 29  is Gln;   A 30  is Lys;   A 31  is Gly or deleted;   A 32  is Lys or deleted;   A 33  is Lys or deleted;   A 34  is Asn or deleted;   A 35  is Asp or deleted;   A 36  is Trp or deleted;   A 37  is Lys or deleted;   A 38  is His or deleted;   A 39  is Asn or deleted;   A 40  is Ile, A5c, or deleted;   A 41  is Thr, A5c, or deleted;   A 42  is Gln or deleted;   A 43  is His, Cys(succinimide-N—(CH 2 ) 11 —CH 3 ), Orn(N—C(O)—(CH 2 ) 10 —CH 3 ), or deleted; and   provided that the compound contains at least one amino acid substitution or modification at positions 4 to 43;   or a pharmaceutical salt thereof.   
     
     
         3 . A compound according to  claim 2 , wherein said compound is:
 (4Hppa 1 , Aib 2 , A5c 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:4);   (4Hppa 1 , Aib 2, 11 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:5);   (4Hppa 1 , Aib 2 , A5c 7 )hGIP(1-30)-NH 2  (SEQ ID NO:6);   (4Hppa 1 , Aib 2, 11 )hGIP(1-30)-NH 2  (SEQ ID NO:7);   (4Hppa 1 , Aib 2 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:8);   (4Hppa 1 , Aib 2 )hGIP(1-30)-NH 2  (SEQ ID NO:9);   (4Hppa 1 , 4Hyp 3 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:10);   (4Hppa 1 , hPro 3 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:11);   (4Hppa 1 , Aib 2 , hPro 3 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:12);   (His 1 , Aib 2, 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:13);   (3,5Br-Tyr 1 , Aib 2, 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:14);   (His 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:15);   (3,5Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:16);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:17);   (3Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:18);   (3I-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:19);   (3,5I-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:20);   (4NH 2 -Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:21);   (hTyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:22);   (Cpa 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:23);   (4NH 2 CH 2 -Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:24);   (3,4,5F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:25);   (3F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:26);   (3,4F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:27);   (3,5F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:28);   (3OH-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:29);   (3OH-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:30);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:31);   [Tyr(Ac) 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:32);   (2,6Me-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:33);   [Tyr(Me) 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:34);   (4F-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:35);   (4-Pal 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:36);   (3-Pal 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:37);   (Taz 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:38);   (3NO 2 -Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:39);   (3Thi 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:40);   (4CN-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:41);   (3F-Tyr 1 , Gly 2 , A5c 11, 40 )hGIP(1-42)-OH (SEQ ID NO:42);   (3F-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:44);   (3Cl-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:45);   (3Br-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:46);   (3Cl-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:47);   (3Br-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:48);   (β-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:49);   (3F-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:50);   (2F-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:51);   (αMe-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:52);   (3NH 2 -Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:53);   (2-Pal 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:54);   [3(HO—(CH 2 )Tyr 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:55);   (2,6Me-Tyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:56);   (2,6Me-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:57);   (2,6Me-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:58);   (3F-Phe 1 , Aib 2 , A5c 11, 14, 41 )hGIP(1-42)-OH (SEQ ID NO:59);   (3F-Phe 1 , Aib 2 , A5c 11, 41 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:60);   (3F-Phe 1 , Aib 2 , A5c 11, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:61);   (3F-Phe 1 , Aib 2 , A5c 11, 14, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:62);   (3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH;   (3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , HiS 43 )hGIP(1-43)-OH;   (3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:63);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:64);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:65);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:66);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH;   (3Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:67);   (3Br-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:68);   (3MeO-Tyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:69);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:70);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 14, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:71);   (4CF 3 -Phe 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:72);   (7HO-Tic 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:73);   (4Me-Phe 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:74);   (4CN-Phe 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:75);   (hTyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:76);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:77);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:78);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 )hGIP(1-43)-OH (SEQ ID NO:79);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide)]hGIP(1-43)-OH; or   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide)]hGIP(1-43)-OH;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A compound according to  claim 2 , wherein: A 1  is 4Hppa; A 43  is deleted; and at least one of A 2 , A 3 , A 7 , A 11  and A 14  is not the amino acid residue of the corresponding position in the native GIP; or a pharmaceutical salt thereof. 
     
     
         5 . A compound according to  claim 4 , wherein said compound is:
 (4Hppa 1 , Aib 2 , A5c 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:4);   (4Hppa 1 , Aib 2, 11 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:5);   (4Hppa 1 , Aib 2 , A5c 7 )hGIP(1-30)-NH 2  (SEQ ID NO:6);   (4Hppa 1 , Aib 2, 11 )hGIP(1-30)-NH 2  (SEQ ID NO:7);   (4Hppa 1 , Aib 2 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:8);   (4Hppa 1 , Aib 2 )hGIP(1-30)-NH 2  (SEQ ID NO:9);   (4Hppa 1 , 4Hyp 3 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:10);   (4Hppa 1 , hPro 3 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:11); or   (4Hppa 1 , Aib 2 , hPro 3 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:12);   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A compound according to  claim 2 , wherein: A 1  is Tyr(Ac), Tyr(Me), β-Tyr, 3Br-Tyr, 3,5Br-Tyr, 3Cl-Tyr, 2F-Tyr, 3F-Tyr, hTyr, 3I-Tyr, 3,5I-Tyr, αMe-Tyr, 2,6Me-Tyr, 3MeO-Tyr, 3NH 2 -Tyr, 3NO 2 -Tyr, 3OH-Tyr, or 3(HO—(CH 2 )Tyr; A 2  is A5c, A6c, Aib, D-Ala, Gly, or Ser; and at least one of A 3 , A 11 , A 13 , A 14 , A 40 , A 41  and A 43  is not the amino acid residue of the corresponding position in the native GIP; or a pharmaceutical salt thereof. 
     
     
         7 . A compound according to  claim 6 , wherein: A 2  is Aib, D-Ala, or Gly; and at least two of A 3 , A 11 , A 13 , A 14 , A 40 , A 41  and A 43  are not the amino acid residues of the corresponding positions in the native GIP; or a pharmaceutical salt thereof. 
     
     
         8 . A compound according to  claim 7 , wherein said compound is:
 (3,5Br-Tyr 1 , Aib 2, 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:14);   (3,5Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:16);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:17);   (3Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:18);   (3I-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:19);   (3,5I-Tyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:20);   (hTyr 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:22);   (3OH-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:30);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:31);   [Tyr(Ac) 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:32);   (2,6Me-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:33);   [Tyr(Me) 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:34);   (3NO 2 -Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:39);   (3F-Tyr 1 , Gly 2 , A5c 11, 40 )hGIP(1-42)-OH (SEQ ID NO:42);   (3Cl-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:47);   (3Br-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:48);   (β-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:49);   (3F-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:50);   (2F-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:51);   (αMe-Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:52);   (3NH 2 -Tyr 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:53);   [3(HO—(CH 2 )Tyr 1 , Aib 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:55);   (2,6Me-Tyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:56);   (2,6Me-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:57);   (2,6Me-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:58);   (3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH;   (3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH;   (3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:63);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:64);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:65);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:66);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Orn 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 11 —CH 3 )]hGIP(1-43)-OH;   (3Br-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:67);   (3Br-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:68);   (3MeO-Tyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:69);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:70);   (3MeO-Tyr 1 , Aib 2 , A5c 11, 14, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:71);   (hTyr 1 , Aib 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:76);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH;   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:77);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Lys 43 (N—C(O)—(CH 2 ) 10 —CH 3 )]hGIP(1-43)-OH (SEQ ID NO:78);   (3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 )hGIP(1-43)-OH (SEQ ID NO:79);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide)]hGIP(1-43)-OH; or   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide)]hGIP(1-43)-OH;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . A compound according to  claim 2 , wherein: A 1  is 3Br-Phe, 3Cl-Phe, 4CN-Phe, 3F-Phe, 4F-Phe, 3,4F-Phe, 3,4,5F-Phe, 3,5F-Phe, 4NH 2 -Phe, 4NH 2 CH 2 -Phe, or 3OH-Phe; A 2  is A5c, A6c, Aib, D-Ala, Gly, or Ser; A 1l  is A5c; and at least one of A 14  and A 41  is not the amino acid residue of the corresponding position in the native GIP; or a pharmaceutical salt thereof. 
     
     
         10 . A compound according to  claim 9 , wherein: A 2  is Aib; or a pharmaceutical salt thereof. 
     
     
         11 . A compound according to  claim 10 , wherein said compound is:
 (4NH 2 -Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:21);   (4NH 2 CH 2 -Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:24);   (3,4,5F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:25);   (3F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:26);   (3,4F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:27);   (3,5F-Phe 1 , Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:28);   (3OH-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:29);   (4F-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:35);   (4CN-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:41);   (3F-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:44);   (3Cl-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:45);   (3Br-Phe 1 , Aib 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:46);   (3F-Phe 1 , Aib 2 , A5c 11, 14,41 )hGIP(1-42)-OH (SEQ ID NO:59);   (3F-Phe 1 , Aib 2 , A5c 11, 41 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:60);   (3F-Phe 1 , Aib 2 , A5c 11, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:61); or   (3F-Phe 1 , Aib 2 , A 5 c 11, 14, 41 , His 43 )hGIP(1-43)-OH (SEQ ID NO:62);   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . A compound according to  claim 2 , wherein each amino acid at positions 1, 2 and 3 is substituted or modified; or a pharmaceutical salt thereof. 
     
     
         13 . A compound according to  claim 12 , wherein said compound is (4Hppa 1 , Aib 2 , hPro 3 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:12), or a pharmaceutical salt thereof. 
     
     
         14 . A compound according to  claim 1  or  claim 2 , wherein the peptide bond between A 1  and A 2  is replaced by a pseudopeptide bond, or a pharmaceutical salt thereof. 
     
     
         15 . A compound according to  claim 14 , wherein A 1 -A 2  is A 1 -Ψ-(CH 2 —NH)A 2 , or a pharmaceutical salt thereof. 
     
     
         16 . A compound according to  claim 15 , wherein said compound is [Tyr 1 -Ψ(CH 2 —NH)Gly 2 , A5c 11, 41 ]hGIP(1-42)-OH (SEQ ID NO:43), or a pharmaceutical salt thereof. 
     
     
         17 . A compound according to any one of  claims 1 - 16 , further comprising a covalently linked PEG moiety, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A compound according to  claim 17 , wherein said PEG moiety is covalently linked to the compound via a Cys(maleimide), hCys(maleimide), or Pen(maleimide) linker, to form Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG), or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A compound according to  claim 18 , wherein PEGylation occurs at any one of amino acid residue positions 16, 30, and 31-43, whereby Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of amino acid residue positions 16, 30, and 31-43, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A compound according to  claim 19 , wherein PEGylation occurs at any one of amino acid residue positions 32, 33 and 43, whereby Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of amino acid residue positions 32, 33 and 43, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A compound according to  claim 20 , wherein said PEG moiety has average molecular weight of from about 2,000 to about 80,000, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A compound according to  claim 21 , wherein said PEG is selected from the group consisting of 5K PEG, 10K PEG, 20K PEG, 30K PEG, 40K PEG, 50K PEG, and 60K PEG, to form Cys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG), Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG), Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG), Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG), hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG), hCys(succinimide-N-30K PEG), hCys(succinimide-N-40K PEG), hCys(succinimide-N-50K PEG), hCys(succinimide-N-60K PEG), Pen(succinimide-N-5K PEG), Pen(succinimide-N-10K PEG), Pen(succinimide-N-20K PEG), Pen(succinimide-N-30K PEG), Pen(succinimide-N-40K PEG), Pen(succinimide-N-50K PEG), or Pen(succinimide-N-60K PEG), or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A compound according to any one of  claims 18 - 22 , wherein said succinimide-N-PEG is linear, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A compound according to  claim 23 , wherein said linear succinimide-N-PEG is succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -PEG, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A compound according to any one of  claims 18 - 22 , wherein said succinimide-N-PEG is branched, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A compound according to  claim 25 , wherein said branched succinimide-N-PEG is succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH-PEG-CH 2 -PEG, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A compound according to any one of  claims 22 - 26 , wherein said compound is:
 [3Cl-Tyr 1 , Aib 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-20K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:80);   [3Cl-Tyr 1 , Aib 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-30K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:81);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-20K PEG)]hGIP(1-43)-NH 2;      [3Cl-Tyr 1 , D-Ala 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-30K PEG)]hGIP(1-43)-NH 2;      [3Cl-Tyr 1 , Aib 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-60K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:82);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 43 (succinimide-N-60K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:83);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 ′ Nle 14 , Cys 43 (succinimide-N-60K PEG)]hGIP(1-43)-NH 2;      [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide-N-60K PEG)]hGIP(1-43)-NH 2;      [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:84);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:85);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:86);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-43)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:87);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:88);   [3Cl-Tyr 1 , Aib 2 , A5c 11 , Nle 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:89);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-43)-NH 2 ;   [30-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11 , Nle 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:90);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:91);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:92);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-43)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 -20K PEG)]hGIP(1-42)-NH 2 ;   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-43)-NH 2  (SEQ ID NO:93);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:94);   [3Cl-Tyr 1 , Aib 2 , A5c 11, 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2  (SEQ ID NO:95);   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 43 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-43)-NH 2 ;   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 32 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2 ; or   [3Cl-Tyr 1 , D-Ala 2 , A5c 11, 14 , Cys 33 (succinimide-N—(CH 2 ) 2 —C(O)NH—(CH 2 ) 3 —O—CH 2 —CH(20K PEG)-CH 2 -20K PEG)]hGIP(1-42)-NH 2 ;   or a pharmaceutically acceptable salt thereof.   
     
     
         28 . A pharmaceutical composition comprising an effective amount of a peptide analogue of any one of  claims 1 - 27 . 
     
     
         29 . A pharmaceutical composition of  claim 28 , further comprising a pharmaceutically acceptable carrier. 
     
     
         30 . A method of eliciting an agonist effect from a GIP receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 24  or  claim 25 . 
     
     
         31 . A method of eliciting an antagonist effect from a GIP receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         32 . A method for treating conditions or diseases mediated by GIP-receptor binding, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         33 . The method of  claim 32 , wherein said condition or disease mediated by GIP-receptor binding is selected from the group consisting of type 1 diabetes, type 2 diabetes, obesity, insulin resistance, glucose intolerance, fatty liver, glucagonomas, secretory disorders of the airway, metabolic disorders, arthritis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake and/or losing body weight is desired. 
     
     
         34 . A method for treating diabetes, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         35 . The method of  claim 34 , wherein said diabetes is type 2 diabetes. 
     
     
         36 . A method of treating diabetes-related disorders, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         37 . The method of  claim 36 , wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance. 
     
     
         38 . A method of treating or preventing secondary causes of diabetes, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         39 . The method of  claim 38 , wherein said secondary cause is selected from the group consisting of glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. 
     
     
         40 . A method of treating obesity, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a peptide analogue of any one of  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         41 . A method of stimulating insulin secretion in a subject in need thereof by administering to said subject a therapeutically effective amount of a peptide analogue of any  claims 1 - 27  or a pharmaceutical composition of  claim 28  or  claim 29 . 
     
     
         42 . Use of a peptide analogue of any one of  claims 1 - 27  for the manufacture of a medicament for GIP-receptor binding for the prevention or treatment of diseases or conditions related to impaired binding of GIP-receptor analogues. 
     
     
         43 . Use according to  claim 42  for the manufacture of a medicament for the prevention or treatment of pancreatic beta cell apoptosis. 
     
     
         44 . Use according to  claim 42  for the manufacture of a medicament for the potentiation of glucose dependent proliferation of pancreatic beta cells.