GLP-1 Receptor Agonists Having Improved Pharmacological and Drug Delivery Properties

A polypeptide represented by the following sequence:

• RXN-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-RYC
• wherein
• RXN is the N-terminal group of Xaa1 selected from the group consisting of H and —N(Rx)2,
• wherein each RX is independently selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted formyl, an optionally substituted acetyl, an optionally substituted alkanoyl, an optionally substituted —C(O)-alkyloxy, an optionally substituted —C(O)-aryloxy, an optionally substituted —C(O)-aralkyloxy, an optionally substituted —C(O)-heterocyclyloxy, an optionally substituted —C(O)-heteroarylalkyloxy, an optionally substituted —C(O)NH-alkyl, an optionally substituted —C(O)NH-aryl, an optionally substituted —C(O)NH-arylalkyl, an optionally substituted —SO2-heterocyclyl, an optionally substituted —SO2-alkyl, an optionally substituted —SO2-aryl, an optionally substituted —SO2-arylalkyl, an optionally substituted —SO2-heteroarylalkyl, an optionally substituted —SO2-heteroaryl, and an optionally substituted ureido;
• or
• wherein a first Rx is hydrogen and a second Rx is an amino acid residue Xaa0;
• Xaa0 is an optionally substituted amino acid residue selected from the group consisting of Gly, Pro, Arg, Glu, His, Phe, Trp, and Aib;
• Xaa1 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises an alkyl, aryl or heteroaryl group;
• Xaa2 is an optionally substituted amino acid residue selected from the group consisting of Gly, Aib, Ala, D-Ala, N-methyl-Ala, N-methyl-D-Ala, Pro, α-methyl-Pro, Val, D-Val, and D-His;
• Xaa3 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises a carboxyl or sulfonic acid group;
• Xaa4 is an amino acid residue selected from the group consisting of Gly, Ala, Aib, and β-Ala;
• Xaa5 is an optionally substituted amino acid selected from the group consisting of Thr, Ser, Ala, Aib, Val, α-MeSer, α-MeThr, and α-MeVal;
• Xaa6 is an optionally substituted amino acid residue that is disubstituted at the α carbon, wherein one of the α carbon substituents is an optionally substituted aryl or an optionally substituted heteroaryl;
• Xaa7 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises a hydroxyl group;
• Xaa8 is an optionally substituted amino acid residue selected from the group consisting of Ser, His, and Asn;
• Xaa9 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises a carboxyl or sulfonic acid group;
• Xaa10 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises a sulfide, an optionally substituted aryl an optionally substituted heteroaryl, or any combination thereof;
• Xaa11 is an optionally substituted amino acid residue comprising an amino acid side chain that comprises a sulfide group, an optionally substituted aryl, an optionally substituted heteroaryl, or any combination thereof;
• and
• RYC is the C-terminal group of Xaa11 having the structure —C(O)N(RY)2, wherein each RY is independently hydrogen or a PK modifier group, wherein the PK modifier group improves the pharmacokinetic profile of the polypeptide.