Analogues of glucose-dependent insulinotropic polypeptide (GIP) modified at N-terminal

A compound of formula (I),

• (R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-A42-A43-R1, (I)
• wherein:
• A1 is Cpa, His, 4Hppa, 2-Pal, 3-Pal, 4-Pal, 3Br-Phe, 4CF3-Phe, 3Cl-Phe, 4CN-Phe, 3F-Phe, 4F-Phe, 3,4F-Phe, 3,5F-Phe, 3,4,5F-Phe, 4Me-Phe, 4NH2-Phe, 4NH2CH2-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, 3NH2-Tyr, 3NO2-Tyr, 3OH-Tyr, or 3(HO—CH2)Tyr;
• A2 is Ala, Abu, D-Abu, Acc, Aib, β-Ala, D-Ala, Gaba, Gly, Ser, D-Ser, Thr, D-Thr, Val, or D-Val;
• A3 is Glu, Aib, Asp, N-Me-Asp, Dhp, Dmt, N-Me-Glu, 3Hyp, 4Hyp, 4Ktp, Pro, hPro, Thz, or Tic;
• A4 is Gly, Acc, Aib, or β-Ala;
• A5 is Thr, Acc, Aib, or Ser;
• A6 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4, X5, X6, X7, X8)Phe, or Trp;
• A7 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
• A8 is Ser, Aib, or Thr;
• A9 is Asp, Aib, or Glu;
• A10 is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X4, X5, X6, X7, X8)Phe;
• A11 is Ser, Acc, Aib, Nle, or Thr;
• A12 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
• A13 is Ala, Acc, Aib, p-Ala, D-Ala, Gly, or Ser;
• A14 is Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, or Val;
• A15 is Asp, Aib, or Glu;
• A16 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3);
• A17 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
• A18 is His, Amp, Arg, 2-Pal, 3-Pal, 4-Pal, Phe, or Tyr;
• A19 is Gln, Aib, or Asn;
• A20 is Gln, Aib, or Asn;
• A21 is Asp, Aib, or Glu;
• A22 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4, X5, X6, X7, X8)Phe, or Trp;
• A23 is Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle;
• A24 is Asn, Aib, or Gln;
• A25 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X4, X5, X6, X7, X8)Phe;
• A26 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4, X5, X6, X7, X8)Phe, or Tle;
• A27 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4, X5, X6, X7, X8)Phe, or Tle;
• A28 is Ala, Acc, or Aib;
• A29 is Gln, Aib, Asn, or deleted;
• A30 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A31 is Gly, Aib, Acc, β-Ala, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH2), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A32 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A33 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A34 is Asn, Aib, Gln, Ser, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A35 is Asp, Aib, Glu, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A36 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, (X4, X5, X6, X7, X8)Phe, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A37 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A38 is His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A39 is Asn, Aib, Gln, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A40 is Ile, Acc, Aib, Ser, Thr, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A41 is Thr, Acc, Aib, Asn, Gln, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A42 is Gln, Acc, Aib, Asn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• A43 is Acc, Ado, Aib, Ala, Asn, Asp, His, Gln, Phe, Thr, Trp, Orn(N—C(O)—(CH2)10—CH3), HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted;
• R1 is OH, NH2, (C1-C30)alkoxy, or NH—X2—CH2—Z0, wherein X2 is a (C0-C30) hydrocarbon moiety and Z0 is H, OH, CO2H, or CONH2;
• each of R2, R3, R4 and R5 is independently selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C1-C30)acyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, substituted aryl(C1-C30)alkyl, and substituted aryl(C1-C30)acyl;
• provided that when R2 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R3 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, or substituted aryl(C1-C30)alkyl;
• further provided that when R4 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R5 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, or substituted aryl(C1-C30)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;
• X4, X5, X6, X7 and X8 each is, independently for each occurrence, H, F, CF3, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, aryl, substituted aryl, OH, NH2, —CH2NH2, NO2, or CN;
• wherein the bond between A1 and A2 is a peptide or pseudopeptide bond;
• and
• wherein the compound optionally further comprises a covalently linked PEG moiety;
• provided that when A1 is 4Hppa, then R2 and R3 are deleted;
• further provided that at least one amino acid residue at positions 2 and 3 is not the amino acid residue of the corresponding position in native hGIP;
• and
• further provided that at least one amino acid residue at positions 7, 11, 13, 14, 40, 41, and 43 is not the amino acid residue of the corresponding position in native hGIP;
• or a pharmaceutically acceptable salt thereof.