Analogs of ghrelin substituted at the N-terminal

A ghrelin analog compound according to formula (I):

• (R2)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-R1 (I)
• wherein:
• A1 is Inp, 1-Apc or 4-Apc;
• A2 is Ser, Abu, Acc, Act, Aib, Ala, Ava, Thr or Val;
• A3 is Ser, Asp(NH—R3), Asp(O—R4), Cys(S—R5), Dab(S(O)2—R6), Dap(S(O)2—R7), Glu(NH—R8), Glu(O—R9), Ser(C(O)—R10), Thr(C(O)—R11) or HN—CH((CH2)n—N(R12R13))—C(O);
• A4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X1,X2,X3,X4,X5)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
• A5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
• A6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
• A7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
• A8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH2)n—N(R12R13))—C(O);
• A9 is His, Acc, Apc, Aib, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X1,X2,X3,X4,X5-)Phe, Taz, 2-Thi or 3-Thi;
• A10 is Gln, Acc, Aib, Asn, Asp or Glu;
• A11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn or HN—CH((CH2)n—N(R12R13))—C(O);
• A12 is Val, Abu, Acc, Aib, Ala, Cha, Gly, Ile, Leu, Nle, Nva or Tle;
• A13 is Gln, Acc, Aib, Asn, Asp or Glu;
• A14 is Gln, Acc, Aib, Asn, Asp or Glu;
• A15 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys or Orn;
• A16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
• A17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R3), Asp(O—R4), Cys(S—R5), Dab(S(O)2—R6), Dap(S(O)2—R7), Glu(NH—R8), Glu(O—R9), Ser(C(O)—R10), Thr(C(O)—R11), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
• A18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val or deleted;
• A19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
• A20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
• A21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
• A22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
• A23 is Ala, Abu, Acc, Act, Aib, Apc, Gly, Nva, Val or deleted;
• A24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
• A25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
• A26 is Gln, Aib, Asn, Asp, Glu or deleted;
• A27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
• A28 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
• R1 is —OH, —NH2, —(C1-C30)alkoxy or NH—X6—CH2—Z0, wherein X6 is a (C1-C12)alkyl or (C2-C12)alkenyl and Z0 is —H, —OH, —CO2H or —C(O)—NH2;
• R2 is, H, (C1-C30)alkyl, (C1-C30)heteroallcyl, (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 (C2-C30)acyl, substituted (C2-C30)alkenyl, substituted aryl(C1-C30)alkyl, substituted (C2-C30)alkynyl or substituted aryl(C1-C30)acyl;
• each of R3, R4, R5, R6, R7, R8, R9, R10 and R11 is, independently for each occurrence thereof, selected from the group consisting of (C1-C40)alkyl, (C2-C40)alkenyl, substituted (C1-C40) alkyl, substituted (C2-C40) alkenyl, alkylaryl, substituted alkylaryl, aryl and substituted aryl;
• each of R12 and R13 is, independently for each occurrence thereof, selected from the group consisting of H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, aryl(C1-C40)acyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroallcyl, substituted (C1-C40)acyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, substituted aryl(C1-C40)alkyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl or —C(NH)—NH2;
• n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
• each of X1, X2, X3, X4, and X5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, aryl, substituted aryl, OH, NH2, NO2 and CN;
• provided that:
• when R12 is (C1-C40)acyl, aryl(C1-C40)acyl, substituted (C1-C40)acyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, or —C(NH)—NH2, then R13 is H or (C1-C40)alkyl, (C1-C40)heteroalkyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, or substituted aryl(C1-C40)alkyl;
• or a pharmaceutically acceptable salt thereof.