Analogues of glucose-dependent insulinotropic polypeptide

Abstract

There is provided a series of glucose-dependent insulinotropic polypeptide analog compounds, pharmaceutical compositions, and the use of the GIP polypeptide analog compounds as GIP-receptor agonists or antagonists for the 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 )-Tyr-Ala-Glu-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 Tyr, 4Hppa, or HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O); 
 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, NMe-Asp, Dhp, Dmt, Glu, NMe-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, fl-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(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 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—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 ),—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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—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 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 31  is Gly, Acc, Aib, β-Ala, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 ),—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), His, 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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—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 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 33  is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—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 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 34  is Asn, Aib, Gln, Ser, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 35  is Asp, Aib, Glu, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—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 ),—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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CI - 1 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(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 49  is Ile, Acc, Aib, Ser, Thr, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—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 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 ) x —C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 42  is Gln, Acc, Aib, Asn, HN—CH((CH 2 )—N(R 4 R 5 ))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Pen(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ),—CH 3 ), Cys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), hCys(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), Pen(succinimide-N—(CH 2 ),—NH—C(O)—(CH 2 ) t —CH 3 ), or deleted; 
 A 43  is Acc, Aib, Ala, Asp, Gln, His, 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 )—C(O)—NH—(CH 2 ) y —CH 3 ), hCys(succinimide-N—(CH 2 )—C(O)—NH—(CH 2 ) y —CH 3 ), Pen(succinimide-N—(CH 2 )—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° 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, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 , or CN; 
 provided that when A 1  is 4Hppa, then R 2  and R 3  are deleted; 
 further provided that only one amino acid at positions 1, 2 and 3 of the compound is substituted or modified; and 
 further provided that a compound of formula (I) is not (D-A1a 2 )hGIP(1-42), (Pro 3 )hGIP(1-42) (SEQ ID NO:120), (Aib 3 )hGIP(1-42) (SEQ ID NO:121), (Ser 2 )hGIP(1-42) (SEQ ID NO:122), (Abu 2 )hGIP(1-42) (SEQ ID NO:123), (D-Abu 2 )hGIP(1-42), (D-S er 2 )hGIP(1-42), (D-Thr 2 )hGIP(1-42), or (D-Va1 2 )hGIP(1-42); 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein:
 A 1  is Tyr, 4Hppa, or Orn(N—C(O)—(CH 2 ) 12 —CH 3 );   A 2  is Ala, A5c, A6c, Aib, D-Ala, Gly, or Ser;   A 3  is Glu, Dhp, 3Hyp, 4Hyp, Pro, hPro, or Tic;   A 4  is Gly or Aib;   A 5  is Thr, A5c, or Aib;   A 6  is Phe or A6c;   A 7  is Ile, A5c, A6c, or Aib;   A 8  is Ser or Aib;   A 9  is Asp or Aib;   A 10  is Tyr;   A 11  is Ser, A5c, A6c, Aib, or Nle;   A 12  is Ile, A5c, or Aib;   A 13  is Ala or Aib;   A 14  is Met, A5c, A6c, or Nle;   A 15  is Asp;   A 16  is Lys;   A 17  is Ile or A6c;   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 or A6c;   A 27  is Leu or A6c;   A 28  is Ala or Aib;   A 29  is Gln;   A 30  is Lys;   A 31  is Gly, Aib, Cys(Psu), His, or deleted;   A 32  is Lys, Cys(Psu), or deleted;   A 33  is Lys, Cys(Psu), or deleted;   A 34  is Asn, Cys(Psu), or deleted;   A 35  is Asp, Cys(Psu), or deleted;   A 36  is Trp, Cys(Psu), or deleted;   A 37  is Lys, Cys(Psu), or deleted;   A 38  is His, Cys(Psu), or deleted;   A 39  is Asn, Cys(Psu), or deleted;   A 40  is Ile, A5c, A6c, Cys(Psu), or deleted;   A 41  is Thr, A5c, A6c, Aib, Cys(Psu), or deleted;   A 42  is Gln or deleted;   A 43  is Cys(Psu), Gln, His, or deleted; and   provided that the compound contains at least one additional amino acid substitution or modification at positions 4-43;   or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A compound according to  claim 2 , wherein said compound is:
 (Aib 2, 11 )hGIP(1-42)-OH (SEQ ID NO:4);   (Aib 2, 9 )hGIP(1-42)-OH (SEQ ID NO:5);   (Aib 2, 7 )hGIP(1-42)-OH (SEQ ID NO:6);   (Aib 2, 5 )hGIP(1-42)-OH (SEQ ID NO:7);   (Aib 2 , A5c 5 )hGIP(1-42)-OH (SEQ ID NO:8);   (Aib 2 , A5c 7 )hGIP(1-42)-OH (SEQ ID NO:9);   (Aib 2 , A5c 12 )hGIP(1-42)-OH (SEQ ID NO:10);   (Aib 2, 12 )hGIP(1-42)-OH (SEQ ID NO:11);   (Aib 2, 8 )hGIP(1-42)-OH (SEQ ID NO:12);   (Aib 2, 4 )hGIP(1-42)-OH (SEQ ID NO:13);   (Aib 2 , A5c 5 )hGIP(1-30)-NH 2  (SEQ ID NO:14);   (Aib 2 , A5c 7 )hGIP(1-30)-NH 2  (SEQ ID NO:15);   (Aib 2 , A5c 12 )hGIP(1-30)-NH 2  (SEQ ID NO:16);   (Aib 2, 4 )hGIP(1-30)-NH 2  (SEQ ID NO:17);   (Aib 2, 5 )hGIP(1-30)-NH 2  (SEQ ID NO:18);   (Aib 2, 7 )hGIP(1-30)-NH 2  (SEQ ID NO:19);   (Aib 2, 8 )hGIP(1-30)-NH 2  (SEQ ID NO:20);   (Aib 2, 9 )hGIP(1-30)-NH 2  (SEQ ID NO:21);   (Aib 2, 11 )hGIP(1-30)-NH 2  (SEQ ID NO:22);   (Aib 2, 12 )hGIP(1-30)-NH 2  (SEQ ID NO:23);   (Aib 2, 13 , A6c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:24);   (Aib 2, 31 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:25);   (Aib 2, 41 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:26);   (Aib 2, 31 , A6c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:27);   (Aib 2, 41 , A6c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:28);   (Aib 2 , A6c 7, 26 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:29);   (Aib 2 , A6c 7, 27 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:30);   (Aib 2 , A6c 7, 40 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:31);   (Aib 2 , A6c 7, 41 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:32);   (Aib 2, 28 , A6c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:33);   (Aib 2 , A6c 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:34);   (Aib 2 , A5c 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:35);   (Aib2, 11, Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:36);   (A5c 2, 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:37);   (Aib 2 , A5c 7, 14 )hGIP(1-30)-NH 2  (SEQ ID NO:38);   (A6c 2, 7 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:39);   (Aib 2 , A6c 7, 17 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:40);   (Aib2, 11, A6c 14 )hGIP(1-30)-NH 2  (SEQ ID NO:41);   (Aib 2 , A6c 7, 14 )hGIP(1-30)-NH 2  (SEQ ID NO:42);   (A5c 2 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:43);   (Aib2, 11, A6c 14 )hGIP(1-42)-OH (SEQ ID NO:44);   (Aib 2 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:45);   (Aib 2 , A6c 7 )hGIP(1-42)-OH (SEQ ID NO:46);   (Aib 2 , A5c 7 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:47);   (Aib2, 11, Nle 14 )hGIP(1-42)-OH (SEQ ID NO:48);   (Aib 2 , A5c 11 )hGIP(1-30)-NH 2  (SEQ ID NO:49);   (Aib 2, 13 )hGIP(1-30)-NH 2  (SEQ ID NO:50);   (Aib 2 , A5c 11 , A6c 14 )hGIP(1-30)-NH 2  (SEQ ID NO:51);   (Aib 2, 13 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:52);   (Aib 2 , A5c 11 , Nle 14 )hGIP(1-30)-NH 2  (SEQ ID NO:53);   (Aib 2 , A6c 7, 14 )hGIP(1-42)-OH (SEQ ID NO:54);   (Aib 2 , A6c 7 )hGIP(1-30)-NH 2  (SEQ ID NO:55);   (Aib 2 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:56);   (Aib 2 , A5c 11 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:57);   (Aib 2 , A6c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:58);   (A5c 2, 7 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:59);   (Aib 2, 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:60);   (Aib 2 , A5c 7 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:61);   (Aib 2 , A5c 7, 14 )hGIP(1-42)-OH (SEQ ID NO:62);   (Aib 2, 13 )hGIP(1-42)-OH (SEQ ID NO:63);   (Aib 2 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:64);   (Pro 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:65);   (hPro 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:66);   (Dhp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:67);   (hPro 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:68);   (Tic 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:69);   (4Hyp 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:70);   (4Hyp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:71);   (Tic 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:72);   (3Hyp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:73);   (Tic 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:74);   (hPro 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:75);   [Aib 2 , A6c 7 , Cys(Psu) 41 ]hGIP(1-42)-OH (SEQ ID NO:76);   (hPro 3 , A5 c 11 )hGIP(1-42)-OH (SEQ ID NO:77);   (Pro 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:78);   (Pro 3 , A5c 7, 14 )hGIP(1-42)-OH (SEQ ID NO:79);   (Pro 3 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:80);   [Aib 2 , A6c 7 , Cys(Psu) 40 ]hGIP(1-42)-OH (SEQ ID NO:81);   [Aib 2 , A6c 7 , Cys(Psu) 39 ]hGIP(1-42)-OH (SEQ ID NO:82);   [Aib 2 , A6c 7 , Cys(Psu) 38 ]hGIP(1-42)-OH (SEQ ID NO:83);   [Aib 2 , A6c 7 , Cys(Psu) 36 ]hGIP(1-42)-OH (SEQ ID NO:84);   (Tic 3 , A5 c 11 )hGIP(1-42)-OH (SEQ ID NO:85);   (hPro 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:86);   (4Hyp 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:87);   [Aib 2 , A6c 7 , Cys(Psu) 35 ]hGIP(1-42)-OH (SEQ ID NO:88);   [Aib 2 , A6c 7 , Cys(Psu) 34 ]hGIP(1-42)-OH (SEQ ID NO:89);   (4Hyp 3 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:90);   (4Hyp 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:91);   (Tic 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:92);   [Aib 2 , A6c 7 , Cys(Psu) 31 ]hGIP(1-42)-OH (SEQ ID NO:93);   (Pro 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:94);   (Pro 3 , A5c 11 , Nle 14 )hGIP(1-30)-OH (SEQ ID NO:95);   (Aib 2 , A6c 7 , Gln 43 )hGIP(1-43)-OH (SEQ ID NO:96);   [Aib 2 , A6c 7 , Cys(Psu) 32 ]hGIP(1-42)-OH (SEQ ID NO:97);   [Aib 2 , A6c 7 , Cys(Psu) 43 ]hGIP(1-43)-OH (SEQ ID NO:98);   (Pro 3 , A5c 11 , A6c 14 )hGIP(1-30)-NH 2  (SEQ ID NO:99);   (Pro 3 , A6c 7 )hGIP(1-30)-NH 2  (SEQ ID NO:100);   (Pro 3 , A5c 11 )hGIP(1-30)-NH 2  (SEQ ID NO:101);   [Aib 2 , A6c 7 , Cys(Psu) 33 ]hGIP(1-42)-OH (SEQ ID NO:102);   [Aib 2 , A6c 7 , Cys(Psu) 37 ]hGIP(1-42)-OH (SEQ ID NO:103);   (4Hppa 1 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:104);   (Pro 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:105);   [Orn 1 (N—C(O)—(CH 2 ) 12 —CH 3 ), A6c1hGIP(1-42)-OH (SEQ ID NO:106);   (D-Ala 2 , A5 c  1 l, 40 )hGIP(1-42)-OH;   (D-Ala 2 , A5c 11 , His 43 )hGIP(1-43)-OH;   (D-Ala 2 , A5c 11, 41 )hGIP(1-42)-OH;   (D-Ala 2 , A6c 11, 14, 41 )hGIP(1-42)-OH;   (Gly 2 , A6c 11, 14, 41 )hGIP(1-42)-OH (SEQ ID NO:113);   (Gly 2 , Aib 13 , A5c 40 )hGIP(1-42)-OH (SEQ ID NO:114);   (Gly 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:115);   (Gly 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:116);   (Gly 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:117);   (D-Ala 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH;   (D-Ala 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH;   (D-Ala 2 , A5c 11, 14 )hGIP(1-30)-NH 2 ;   (D-Ala 2 , A5c 11 , His 31 )hGIP(1-31)-NH 2 ; or   (Aib 2 , A5c 11, 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:118);   or a pharmaceutical salt thereof.   
     
     
         4 . A compound according to  claim 2 , wherein A 2  is D-Ala, or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound according to  claim 2 , wherein A 31  to A 43  are deleted, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A compound consisting essentially of a sequence of the first 30 consecutive amino acid residues from the N-terminal end of the native hGIP amino acid sequence, wherein: the sequence comprises A5c, A6c, Aib, D-Ala, Gly or Ser substitution at position 2, and at least one additional amino acid substitution or modification at positions 3-30; or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A compound according to  claim 6 , wherein: A 2  is Aib; A 3  is Pro; and at least one of A 7 , A 11 ,A 13  and A 14  is not the amino acid residue of the corresponding position in the native GIP; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A compound according to  claim 2 , wherein: A 2  is Ala, A5c, A6c, or Gly; and A 3  is Glu, Dhp, 3Hyp, 4Hyp, hPro, or Tic; or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A compound according to  claim 8 , wherein said compound is:
 (hPro 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:66);   (Dhp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:67);   (hPro 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:68);   (Tic 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:69);   (4Hyp 3 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:70);   (4Hyp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:71);   (Tic 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:72);   (3Hyp 3 , Aib 13 , Nle 14 )hGIP(1-42)-OH (SEQ ID NO:73);   (Tic 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:74);   (hPro 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:75);   (hPro 3 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:77);   (Tic 3 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:85);   (hPro 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:86);   (4Hyp 3 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:87);   (4Hyp 3 , A5c 11 )hGIP(1-42)-OH (SEQ ID NO:90);   (4Hyp 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:91);   (Tic 3 , A5c 11 , A6c 14 )hGIP(1-42)-OH (SEQ ID NO:92);   (4Hppa 1 , Aib 13 )hGIP(1-42)-OH (SEQ ID NO:104);   [Orn 1 (N—C(O)—(CH 2 ) 12 —CH 3 ), A6cIliGIP(1-42)-OH (SEQ ID NO:106);   (Gly 2 , Abe 11, 14, 41 )hGIP(1-42)-OH (SEQ ID NO:113);   (Gly 2 , Aib 13 , A5c 40 )hGIP(1-42)-OH (SEQ ID NO:114);   (Gly 2 , A5c 11, 41 )hGIP(1-42)-OH (SEQ ID NO:115);   (Gly 2 , A5c 11 , His 43 )hGIP(1-43)-OH (SEQ ID NO:116); or   (Gly 2 , A5c 11 , Nle 14 , His 43 )hGIP(1-43)-OH (SEQ ID NO:117);   or a pharmaceutical salt thereof.   
     
     
         10 . A compound according to  claim 1 , further comprising a covalently linked PEG moiety, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A compound according to  claim 10 , wherein said PEG moiety has average molecular weight of from about 2,000 to about 80,000, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . 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 compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , 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 andor losing body weight is desired. 
     
     
         15 . A method of treating diabetes-related disorders, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         16 . The method of  claim 15 , 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. 
     
     
         17 . 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 compound of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein said secondary cause is selected from the group consisting of glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. 
     
     
         19 . A method of treating obesity, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         20 . A method of stimulating insulin secretion in a subject in need thereof by administering to said subject a therapeutically effective amount of a compound of  claim 1 .