Lipidated amide-based insulin prodrugs

An insulin prodrug comprising the structure:

• M1-A-B-C-Q;
• wherein Q is an insulin peptide;
• A is an amino acid comprising a side chain covalently linked to a moiety that irreversibly binds to a plasma protein, optionally wherein said moiety is linked to the side chain of A via a spacer, said spacer comprising one or two charged amino acids;
• B is an N-alkylated amino acid;
• C is an amide bond, X70 or X70X71;
• and
• M1 is a serum enzyme cleavable moiety linked to A via the N-terminal amine of A, wherein
• X70 and X71 are amino acids with a side chain independently selected from the group consisting of H, (C1-C4 alkyl)COOH, (C1-C4 alkyl)SO3H, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, further wherein A-B-C is linked to Q through an amide bond via an aliphatic amino group of Q, said aliphatic amino group selected from the alpha amino group on the N-terminal amino acid of the A chain or the B chain, or an aliphatic amino group on a side chain of an B3, B28 or B29 amino acid of Q.

An insulin prodrug comprising the structure:

• A-B-C-Q;
• wherein Q is an insulin peptide;
• and
• A-B-C comprises the structure:
• wherein
• A-B-C is linked to Q through an amide bond via the N-terminal amino acid of the A chain or the B chain, or an aliphatic amino group on a side chain of an B3, B28 or B29 amino acid of Q,
• R1 is selected from the group consisting of H, (C1-C4 alkyl)O—S1—R9, (C1-C4 alkyl)S—S1—R9, (C1-C4 alkyl)CONH—S1—R9, (C1-C4 alkyl)COO—S1—R9, (C1-C6 alkyl)NH—S1—R9, (C1-C6 alkyl)NHR9 and (C0-C4 alkyl)(C6-C10 aryl)-S1—R9;
• R2 and R8 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, (C1-C4 alkyl)OH, (C1-C4 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONHH, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NHH, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or aryl;
• R3 is C1-C18 alkyl, C3-C8 alkenyl, (C1-C4 alkyl)(C4-C6 cycloalkyl), (C1-C4 alkyl)(C3-C5 heterocyclic), (C1-C4 alkyl)(C6-C10 aryl) or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
• R4 is H, C1-C18 alkyl, (C1-C6 alkyl)NHR9 or C1-C6 alkyl)NH—S1—R9,
• R5 is OH, or NHR6;
• R6 is H, C1-C8 alkyl;
• R7 is selected from the group consisting of H, OH and OR9;
• R9 is selected from the group consisting of C16-C30 acyl, and C16-C30 alkyl;
• R11, and R13 are each H or C1-C6 alkyl;
• R10 and R12 are independently selected from the group consisting of H, CH3, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, and CH2(C3—N2 heterocyclic);
• and
• S1 is a bond or a spacer consisting of one to six amino acids, wherein said spacer comprises one or more charged amino acids selected from the group consisting of aspartic acid, glutamic acid, cysteic acid, arginine and lysine, with the proviso that R1 is other than H when R4 is H or C1-C18 alkyl.