Dual GIP and GLP-1 agonist compounds

Abstract

The present invention relates to a pharmaceutical composition comprising a dual enteroinsulinotropic peptide which can simultaneously agonize the human glucose dependent insulin secretogenic polypeptide (GIP) and the receptor of the glucagon-like peptide 1 (GLP-1).

Description

[0001] The present invention relates to the field of medicine. More particularly, the present invention relates to dual incretin peptide mimetic compounds, wherein a single peptide excites the receptors of both human glucose-dependent insulin secretagogue polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such compounds can be used to treat type 2 diabetes (T2D).

[0002] T2D is the most common type of diabetes, accounting for approximately 90% of all diabetes. T2D is characterized by high blood glucose levels caused by insulin resistance. Additional treatment options for T2D are needed. Compounds with dual mechanisms of action of GIP and GLP1 are particularly needed.

[0003] GIP is a 42 amino acid gastrointestinal regulatory peptide that reportedly plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic β cells in the presence of glucose and protecting pancreatic β cells. GLP-1 is a 37 amino acid peptide that reportedly stimulates insulin secretion, protects pancreatic β cells, and inhibits glucagon secretion, gastric emptying, and food intake, leading to weight loss. GIP and GLP-1 are known as incretins; incretin receptor signaling plays physiologically relevant roles that are critical for glucose homeostasis. In normal physiology, GIP and GLP-1 are secreted from the intestine after a meal, and these incretins enhance the physiological response to food, including satiety, insulin secretion, and nutrient processing. Patients with T2D have impaired incretin responses.

[0004] Glucagon is a 29-amino acid peptide produced by the pancreas that, when bound to the glucagon receptor, signals the liver to release glucose, resulting in an increase in blood glucose. GLP-2 is a peptide that, like GLP-1, is processed from proglucagon and is known to be involved in cell proliferation in the intestine. Therefore, during chronic treatment of patients with T2D, stimulation of glucagon and GLP-2 receptors should be minimized to minimize glucose reduction and reduce potential long-term carcinogenic risk.

[0005] Certain GIP analogs have been described in WO 2013 / 164483, WO 2014 / 192284 and WO 2011 / 119657 as exhibiting GIP and GLP-1 activity. In addition, the compound tirzepatide, a GIP / GLP1 receptor agonist peptide, is described and claimed in US Patent 9474780. Tirzepatide has been approved by the US Food and Drug Administration for the treatment of diabetes as an adjunct to diet and exercise.

[0006] DPP IV belongs to the exopeptidase class of proteolytic enzymes. The introduction of unnatural amino acids into the sequence can increase the proteolytic stability of any given peptide against degradation by DPP IV.

[0007] There remains a need to provide additional treatment options for T2D patients. The single peptide compounds of the present invention are dual agonists that simultaneously have GIP and GLP-1 receptor agonism. Such peptides can provide sufficient stability to resist DPP IV and other forms of degradation, while still maintaining low immunogenic potential. Pharmaceutical compositions for use as therapeutic agents are provided.

[0008] Therefore, one embodiment of the present invention provides a compound of formula I:

[0009] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0010] in

[0011] X 22 is F or 1-Nal;

[0012] X 30 Selected from G-NH2, G-OH, GP-OH, GPSSG-NH2 (SEQ ID NO: 15) and GPSSG-OH (SEG ID NO: 5);

[0013] a is 1 or 2;

[0014] b is 1 or 2;

[0015] c is 16 or 18;

[0016] The C-terminal amino acid is optionally amidated to a C-terminal primary amide (SEQ ID NO: 6); or

[0017] or pharmaceutically acceptable salts thereof.

[0018] In one embodiment is a compound of Formula I wherein c is 18, or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, is a compound of the formula:

[0020] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 (SEQ ID NO:7)

[0021] in

[0022] X 22 is F or 1-Nal;

[0023] X 30 Selected from G-NH2, G-OH, GP-OH, GPSSG-NH2 (SEQ ID NO: 15) or GPSSG-OH (SEQ ID NO: 5);

[0024] a is 1 or 2;

[0025] b is 1 or 2;

[0026] c is 16 or 18; or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, is a compound selected from the group consisting of:

[0028] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-NH2 (SEQ ID NO:8);

[0029] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH (SEQ ID NO:9);

[0030] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2 (SEQ ID NO:10);

[0031] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18 -CO2H)-AFVQWLIAGGPSSG-OH (SEQ ID NO: 11);

[0032] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH (SEQ ID NO: 12), or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0034] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0035] in

[0036] X 22 is F or 1-Nal;

[0037] X 30 Selected from G, GP and GPSSG (SEQ ID NO: 5);

[0038] a is 1 or 2;

[0039] b is 1 or 2;

[0040] c is 16 or 18;

[0041] The C-terminal amino acid is optionally amidated to a C-terminal primary amide (SEQ ID NO: 13); or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment is a pharmaceutical composition comprising a compound of Formula I, wherein c is 18, or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0044] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2)c -CO2H)-AX 22 -VQWLIAG-X 30 (SEQ ID NO:14)

[0045] in

[0046] X 22 is F or 1-Nal;

[0047] X 30 Selected from G, GP and GPSSG (SEQ ID NO: 5);

[0048] a is 1 or 2;

[0049] b is 1 or 2;

[0050] c is 16 or 18; or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, is a pharmaceutical composition comprising a compound selected from:

[0052] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-NH2 (SEQ ID NO:8);

[0053] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH (SEQ ID NO:9);

[0054] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2 (SEQ ID NO:10);

[0055] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-OH (SEQ ID NO: 11);

[0056] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH (SEQ ID NO: 12), or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0058] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH; or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0060] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH; or

[0061] A pharmaceutically acceptable salt thereof; further comprising at least one excipient or diluent.

[0062] In one embodiment is a compound of the formula:

[0063] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-KAX 22 -VQWLIAG-X 30

[0064] in

[0065] X 22 is F or 1-Nal;

[0066] X 30 Selected from G, GP and GPSSG;

[0067] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof.

[0068] In one embodiment, is a compound of the formula:

[0069] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-KAX 22-VQWLIAG-X 30

[0070] in

[0071] X 22 is F or 1-Nal;

[0072] X 30 is a GP;

[0073] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0075] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-KAX 22 -VQWLIAG-X 30

[0076] in

[0077] X 22 is F or 1-Nal;

[0078] X 30 Selected from G, GP and GPSSG;

[0079] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, is a pharmaceutical composition comprising a compound of the formula:

[0081] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-KAX 22 -VQWLIAG-X 30

[0082] in

[0083] X 22 is F or 1-Nal;

[0084] X 30 Selected from G, GP and GPSSG;

[0085] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0086] In a further embodiment, the present invention provides a compound of Formula I, wherein a is 2, b is 1; and c is 18; or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the formula:

[0088]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, is a pharmaceutical composition comprising a compound selected from:

[0091] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-NH2

[0092] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-NH2

[0093] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH

[0094] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2

[0095] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-OH; and

[0096] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH; or

[0097] or pharmaceutically acceptable salts thereof.

[0098] In one embodiment, the present invention provides a composition comprising a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0099] in

[0100] X 22 is F or 1-Nal;

[0101] X 30 Selected from G, GP and GPSSG;

[0102] a is 1 or 2;

[0103] b is 1 or 2;

[0104] c is 16 or 18;

[0105] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0106] or pharmaceutically acceptable salts thereof.

[0107] In one embodiment, the present invention provides a composition comprising a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0108] in

[0109] X 22 is F or 1-Nal;

[0110] X 30 Selected from G, GP and GPSSG;

[0111] a is 1 or 2;

[0112] b is 1 or 2;

[0113] c is 16 or 18;

[0114] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

[0115] In one embodiment, the present invention provides a method for treating type 2 diabetes, comprising administering to a patient in need thereof an effective amount of a compound of the formula:

[0116] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0117] in

[0118] X 22 is F or 1-Nal;

[0119] X 30 Selected from G, GP and GPSSG;

[0120] a is 1 or 2;

[0121] b is 1 or 2;

[0122] c is 16 or 18;

[0123] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0124] In a further embodiment, the present invention provides a method for treating type 2 diabetes comprising administering a compound of the formula:

[0125] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 ;

[0126] in

[0127] X 22 is F or 1-Nal;

[0128] X 30 Selected from G, GP and GPSSG;

[0129] a is 1 or 2;

[0130] b is 1 or 2;

[0131] c is 16 or 18;

[0132] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0133] Its pharmaceutically acceptable salt; simultaneously, separately or sequentially with an effective amount of one or more active agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporter. In one embodiment, the present invention provides a method for treating type 2 diabetes, comprising administering a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 ;

[0134] in

[0135] X 22 is F or 1-Nal;

[0136] X 30 Selected from G, GP and GPSSG;

[0137] a is 1 or 2;

[0138] b is 1 or 2;

[0139] c is 16 or 18;

[0140] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0141] or a pharmaceutically acceptable salt thereof; simultaneously, separately or sequentially with an effective amount of one or more active agents selected from GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporters. In one embodiment, the GIP / GLP1 agonist is telportide or a pharmaceutically acceptable salt thereof.

[0142] In one embodiment, the present invention provides a method for improving glycemic control in adults with type 2 diabetes, comprising administering to a patient in need thereof an effective amount of a compound of the formula:

[0143] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 ;

[0144] in

[0145] X 22 is F or 1-Nal;

[0146] X 30 Selected from G, GP and GPSSG;

[0147] a is 1 or 2;

[0148] b is 1 or 2;

[0149] c is 16 or 18;

[0150] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0151] Its pharmaceutically acceptable salt; as an adjunct to diet and exercise. In one embodiment, the present invention provides a method for long-term weight management of adults with an initial body mass index ≥ 27, comprising administering an effective amount of a compound of the formula:

[0152] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0153] in

[0154] X 22 is F or 1-Nal;

[0155] X 30 Selected from G, GP and GPSSG;

[0156] a is 1 or 2;

[0157] b is 1 or 2;

[0158] c is 16 or 18;

[0159] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof; as an adjunct to a low-calorie diet and increased physical activity.

[0160] In one embodiment, the present invention provides a method for long-term weight management in adults with an initial body mass index ≥ 27, comprising administering to a patient in need thereof an effective amount of a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0161] in

[0162] X 22 is F or 1-Nal;

[0163] X 30 Selected from G, GP and GPSSG;

[0164] a is 1 or 2;

[0165] b is 1 or 2;

[0166] c is 16 or 18;

[0167] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0168] or a pharmaceutically acceptable salt thereof; simultaneously, separately or sequentially with an effective amount of one or more active agents selected from GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporters. In one embodiment, the GIP / GLP1 agonist is telportide or a pharmaceutically acceptable salt thereof.

[0169] In one embodiment, the present invention provides a method for treating metabolic syndrome, comprising administering to a patient in need thereof an effective amount of a compound of the formula:

[0170] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0171] in

[0172] X 22 is F or 1-Nal;

[0173] X 30 Selected from G, GP and GPSSG;

[0174] a is 1 or 2;

[0175] b is 1 or 2;

[0176] c is 16 or 18;

[0177] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0178] or pharmaceutically acceptable salts thereof.

[0179] In one embodiment, the present invention provides a method for treating obesity, comprising administering to a patient in need thereof an effective amount of a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in

[0180] X 22 is F or 1-Nal;

[0181] X 30 Selected from G, GP and GPSSG;

[0182] a is 1 or 2;

[0183] b is 1 or 2;

[0184] c is 16 or 18;

[0185] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0186] In a further embodiment, the present invention provides a method for treating dyslipidemia, obesity and / or hepatic steatosis associated with insulin resistance and diabetes, comprising administering an effective amount of a compound of the formula:

[0187] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a-(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0188] in

[0189] X 22 is F or 1-Nal;

[0190] X 30 Selected from G, GP and GPSSG;

[0191] a is 1 or 2;

[0192] b is 1 or 2;

[0193] c is 16 or 18;

[0194] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0195] Its pharmaceutically acceptable salt. In addition, the present invention provides a method for treating frailty or increasing bone strength, which comprises administering an effective amount of a compound of the formula:

[0196] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0197] in

[0198] X 22 is F or 1-Nal;

[0199] X 30 Selected from G, GP and GPSSG;

[0200] a is 1 or 2;

[0201] b is 1 or 2;

[0202] c is 16 or 18;

[0203] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0204] or a pharmaceutically acceptable salt thereof.

[0205] In one embodiment, the present invention provides compounds of the formula:

[0206] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0207] in

[0208] X 22 is F or 1-Nal;

[0209] X 30 Selected from G, GP and GPSSG;

[0210] a is 1 or 2;

[0211] b is 1 or 2;

[0212] c is 16 or 18;

[0213] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0214] Its pharmaceutically acceptable salt; for use in treatment. In a further embodiment, the present invention provides a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0215] in

[0216] X 22 is F or 1-Nal;

[0217] X 30 Selected from G, GP and GPSSG;

[0218] a is 1 or 2;

[0219] b is 1 or 2;

[0220] c is 16 or 18;

[0221] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0222] Its pharmaceutically acceptable salt; used for treating type 2 diabetes. In a further embodiment, the present invention provides the following compound: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0223] in

[0224] X 22 is F or 1-Nal;

[0225] X 30 Selected from G, GP and GPSSG;

[0226] a is 1 or 2;

[0227] b is 1 or 2;

[0228] c is 16 or 18;

[0229] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0230] Its pharmaceutically acceptable salt; combined with one or more active agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporter simultaneously, separately or sequentially for treating type 2 diabetes.

[0231] In a further embodiment, the present invention provides compounds of the formula:

[0232] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0233] in

[0234] X 22 is F or 1-Nal;

[0235] X 30 Selected from G, GP and GPSSG;

[0236] a is 1 or 2;

[0237] b is 1 or 2;

[0238] c is 16 or 18;

[0239] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or

[0240] A pharmaceutically acceptable salt thereof; simultaneously, separately or sequentially in combination with one or more active agents selected from GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporters for the treatment of type 2 diabetes. In one embodiment, the GIP / GLP1 agonist is telportide or a pharmaceutically acceptable salt thereof.

[0241] In one embodiment, the present invention provides compounds of the formula:

[0242] YX1EGTFTSDYSIX2LDKIAQKA X 22 VQWLIAGGPSSGAPPPS

[0243] X1 is Aib; and

[0244] X2 is Aib;

[0245] X 22 Selected from F and 1-Nal;

[0246] or a pharmaceutically acceptable salt thereof.

[0247] In one embodiment, the present invention provides compounds of the formula:

[0248] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0249] X1 is Aib; and

[0250] X2 is Aib; or

[0251] or pharmaceutically acceptable salts thereof.

[0252] In one embodiment, the present invention provides compounds of the formula:

[0253] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0254] X1 is Aib;

[0255] X2 is Aib; and

[0256] K at position 20 is chemically modified using a time extension technique; or a pharmaceutically acceptable salt thereof.

[0257] In one embodiment, the present invention provides compounds of the formula:

[0258] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0259] X1 is Aib;

[0260] X2 is Aib; and

[0261] The C-terminal amino acid was amidated to a C-terminal primary amide;

[0262] or a pharmaceutically acceptable salt thereof.

[0263] In one embodiment, the present invention provides compounds of the formula:

[0264] YX1EGTFTSDYSIX2LDKIAQKAX 22 VQWLIAGGPSSGAPPPSX1 is Aib;

[0265] X2 is Aib;

[0266] X 22 Selected from F and 1-Nal;

[0267] The K at position 20 is optionally chemically modified using time extension techniques; and

[0268] The C-terminal amino acid is optionally amidated to a C-terminal primary amide;

[0269] or a pharmaceutically acceptable salt thereof.

[0270] YX1EGTFTSDYSIX2LDKIAQKA X 22 VQWLIAG-X30, where X1 is Aib;

[0271] X2 is Aib;

[0272] X 22 Selected from F and 1-Nal;

[0273] as well as

[0274] X 30 Selected from G, GP and GPSSG; or

[0275] or pharmaceutically acceptable salts thereof.

[0276] In one embodiment, the present invention provides compounds of the formula:

[0277] YX1EGTFTSDYSIX2LDKIAQKA X 22VQWLIAG-X30, where X1 is Aib;

[0278] X2 is Aib;

[0279] The K at position 20 was chemically modified using a time extension technique;

[0280] X 22 Selected from F and 1-Nal; and

[0281] X 30 Selected from G, GP and GPSSG; or

[0282] or pharmaceutically acceptable salts thereof.

[0283] In one embodiment, the present invention provides compounds of the formula:

[0284] YX1EGTFTSDYSIX2LDKIAQKA X 22 VQWLIAG-X30

[0285] X1 is Aib; and

[0286] X2 is Aib;

[0287] The K at position 20 is optionally chemically modified using a time extension technique;

[0288] X 22 Selected from F and 1-Nal;

[0289] X 30 Selected from G, GP and GPSSG;

[0290] The C-terminal amino acid is optionally amidated to a C-terminal primary amide;

[0291] or a pharmaceutically acceptable salt thereof.

[0292] In one embodiment, the present invention provides compounds of the formula:

[0293] YX1EGTFTSDYSIX2LDKIAQKAX 22 VQWLIAGGPSSGAPPPSX1 is Aib;

[0294] X2 is Aib;

[0295] X 22 Selected from F and 1-Nal; and

[0296] The C-terminal amino acid was amidated to a C-terminal primary amide;

[0297] or a pharmaceutically acceptable salt thereof.

[0298] YX1EGTFTSDYSIX2LDKIAQKA X 22 VQWLIAG-X30

[0299] Where X1 is Aib;

[0300] X2 is Aib;

[0301] X 22 Selected from F and 1-Nal; and

[0302] X 30 Selected from G, GP and GPSSG;

[0303] or a pharmaceutically acceptable salt thereof.

[0304] In one embodiment, the present invention provides compounds of the formula:

[0305] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAG-X30

[0306] Where X1 is Aib;

[0307] X2 is Aib;

[0308] The K at position 20 is optionally chemically modified using a time extension technique;

[0309] X 22 Selected from F and 1-Nal; and

[0310] X 30 Selected from G, GP and GPSSG;

[0311] The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a compound of the present invention for use in glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise. In one embodiment, the present invention provides a compound of the present invention for long-term weight management in adults with an initial body mass index ≥ 27 and with type 2 diabetes as an adjunct to a low-calorie diet and increased physical activity.

[0312] In one embodiment, the present invention provides the use of a compound of the present invention in the preparation of a medicament for the treatment of type 2 diabetes. In a further embodiment, the present invention provides the use of a compound of the present invention in combination with one or more active agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporters simultaneously, individually or sequentially in the preparation of a medicament for the treatment of type 2 diabetes. In a further embodiment, the present invention provides the use of a compound of the present invention in combination with one or more active agents selected from GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose co-transporters simultaneously, individually or sequentially in the preparation of a medicament for the treatment of type 2 diabetes. In a further embodiment, the present invention provides the use of a compound of the present invention simultaneously, separately or sequentially with one or more combinations selected from GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium-glucose co-transporters in the preparation of a medicament for the treatment of type 2 diabetes, wherein the GIP / GLP1 agonist is telportide or a pharmaceutically acceptable salt thereof.

[0313] In one embodiment of the compounds disclosed and / or claimed herein, or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0314] It should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives or pharmaceutically acceptable salts thereof can generally be prepared by performing the methods disclosed in the schemes and / or examples described herein, by substituting an isotope-containing reagent for an isotope-free reagent.

[0315] In one embodiment of the compounds disclosed and / or claimed herein, or pharmaceutically acceptable salts thereof, the compound is a deuterated compound of any one of the compounds described herein, and pharmaceutically acceptable salts thereof.

[0316] In the compounds of the present invention, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise indicated, when an atom is specifically designated as "H" or "hydrogen", the atom is understood to contain hydrogen in its natural abundance isotopic composition. Similarly, unless otherwise indicated, when an atom is specifically designated as "D" or "deuterium", the atom is understood to have a deuterium abundance substantially higher than the natural abundance of deuterium (0.015%).

[0317] As used herein, "time extension technology" refers to peptide time extension technology, such as coupling of peptides to recombinant human serum albumin ("rHSA"), coupling to pharmaceutically acceptable polymers, such as amino acid polymer sequences ("XTEN"), unsulfated heparin-like carbohydrate polymers ("HEP"), hydroxyethyl starch ("HES"), llama heavy chain antibody fragments ("VHH"), pegylation, Fc coupling, bovine serum albumin ("BSA") (Sleep, D. Epert Opin Drug Del (2015) 12, 793-812; Podust VN et al. J Control. Release, 2015; ePUB; Hey, T. et al. in: R. Kontermann (ed.), Therapeutic Proteins: Strategies to Modulate their Plasma Half-Lives, Wiley-VCH Verlag Gmbh & Co. KGaA, Weinheim, Germany, 2012, pp. 117-140; DeAngelis, PL, Drug Dev Delivery (2013) January, 12 / 31 / 2012. In one embodiment, the time extension technique is applied using a linker group. In one embodiment, the time extension technique is applied using 0, 1, 2 or 3 amino acids as a linker. In one embodiment, the time extension technique is in addition to ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H) wherein a is 1 or 2; b is 1 or 2; and c is 16 or 18.

[0318] The present invention provides compounds that exhibit selectivity for GIP and GLP-1 receptors relative to glucagon and GLP-2 receptors. The term "selective" or "selective for" is used herein to refer to GIP and GLP-1 activity compared to glucagon activity, and refers to when the data is normalized from the corresponding in vitro binding assay, the compound exhibits 1000-fold, 500-fold, or about 100-fold higher potency for GIP and GLP-1 relative to glucagon. The term "selective" or "selective for" is used herein to refer to GIP and GLP-1 activity compared to GLP-2 activity, and refers to when the data is normalized from the corresponding in vitro functional assay, the compound exhibits 250-fold, 200-fold, 100-fold, or about 50-fold higher potency for GIP and GLP-1 relative to GLP-2.

[0319] Fatty acids, through their albumin binding motifs, can improve the pharmacokinetics of peptides, for example by extending half-life or by directing the peptide to activate receptors. In one embodiment, peptides without albumin binding motifs can be selected to facilitate more frequent dosing and / or altered receptor binding and / or selectivity.

[0320] The present invention provides a method for treating type 2 diabetes in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. The present invention also provides a method for treating type 2 diabetes in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, wherein the administration is subcutaneous. The present invention also provides a method for treating type 2 diabetes in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, and administering an effective amount of one or more other active ingredients simultaneously, individually or sequentially. In one embodiment, one or more other active ingredients are currently available oral glucose-lowering drugs from a class of drugs that are considered to be the standard of care determined by industry guidelines such as the American Diabetes Association before administration.

[0321] The present invention provides a method for treating long-term weight management in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. The present invention also provides a method for treating long-term weight management in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, wherein the administration is subcutaneous. The present invention also provides a method for treating long-term weight management in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, and administering an effective amount of one or more other active ingredients simultaneously, separately or sequentially.

[0322] The present invention provides a method for treating obesity in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. The present invention also provides a method for treating obesity in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, wherein the administration is subcutaneous. The present invention also provides a method for treating obesity in a patient, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, and administering an effective amount of one or more other active ingredients simultaneously, separately or sequentially.

[0323] The compounds of the present invention utilize a fatty acid to chemically couple with the ε-amino group of the lysine side chain. The fatty acid is coupled with the ε-amino group of the lysine side chain via a linker. The linker includes [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu) a, wherein a is 1 to 2. The compounds of the present invention contain a lysine at position 20, which is obtained by replacing it with ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu) a -CO-(CH2) b -CO2H is chemically modified by coupling with the ε-amino group of the K side chain, wherein a is 1 to 2 and b is 10 to 20. As shown in the chemical structure of Example 1, the [2-(2-amino-ethoxy)-ethoxy]-acetyl group of the first unit is connected to the ε-amino group of the lysine side chain. Then, the [2-(2-amino-ethoxy)-ethoxy]-acetyl group of the second unit is connected to the amino group of the [2-(2-amino-ethoxy)-ethoxy]-acetyl group of the first unit. Then, the γGlu of the first unit is connected to the amino group of the [2-(2-amino-ethoxy)-ethoxy]-acetyl group of the second unit through the γ-carboxyl group of the side chain. When a=2, the γGlu of the second unit is connected to the α-amino group of the first unit γGlu through the γ-carboxyl group of the side chain. Finally, the symmetric fatty acid is connected to the α-amino group of the first unit (when a=1) or the second unit (when a=2) γGlu.

[0324] The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration by parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal). Such pharmaceutical compositions and methods for their preparation are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (DB Troy, ed., 21st ed., Lippincott, Williams & Wilkins, 2006). The preferred route of administration is subcutaneous.

[0325] The compounds of the present invention can react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts and common methods of preparing them are well known in the art. See, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Second Revised Edition (Wiley-VCH, 2011); SM Berge, et al. "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977. Pharmaceutically acceptable salts of the present invention include, but are not limited to, trifluoroacetate, hydrochloride, and acetate.

[0326] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the invention or a pharmaceutically acceptable salt thereof, which, after being administered to the patient in a single dose or multiple doses, provides the desired effect in the patient being diagnosed or treated. The effective amount can be determined by the attending diagnostician (as one skilled in the art) by using known techniques and by observing the results obtained in similar situations. In determining the effective amount for a patient, the attending diagnostician will consider many factors, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant medication; and other relevant circumstances.

[0327] As used herein, the term "treating" includes inhibiting, slowing, halting or reversing the progression or severity of an existing symptom or disorder.

[0328] As used herein, "GIP / GLP1 agonist" refers to a treatment whose pharmacological activity is to agonize both GIP and GLP1 receptors. In one embodiment, a "GIP / GLP1 agonist" is a peptide. In one embodiment, a "GIP / GLP1 agonist" is telportide or a pharmaceutically acceptable salt thereof.

[0329] Some compounds of the present invention are usually effective in a wide dosage range. For example, the dosage of once a week administration can fall within the range of about 0.05 to about 30 mg per person per week. Some compounds of the present invention can be administered every day. In addition, some compounds of the present invention can be administered once a week.

[0330] The amino acid sequences of the present invention contain the standard single-letter or three-letter codes for the twenty naturally occurring amino acids. In addition, "Aib" is alpha-aminoisobutyric acid, and "1-Nal" is 1-naphthylalanine.

[0331] The present invention also encompasses novel intermediates and methods for synthesizing the compounds of the present invention or their pharmaceutically acceptable salts. The intermediates and compounds of the present invention can be prepared by various methods known in the art. In particular, the method using chemical synthesis is described in the following examples. The specific synthesis steps of each of the described approaches can be combined in different ways to prepare the compounds of the present invention or their salts. Reagents and starting materials can be easily obtained by those of ordinary skill in the art. It should be understood that these examples are not intended to limit the scope of the present invention in any way. Example 1

[0332] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2- (γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH(SEQ ID NO:12)

[0333] The structure of SEQ ID NO: 12 is described as follows using the standard single letter amino acid code, with the exception of residues Aib2, Aib13 and K20, where the structures of these amino acid residues have been expanded:

[0334]

[0335] The peptide backbone of Example 1 was synthesized using fluorenylmethoxycarbonyl (Fmoc) / tert-butyl (t-Bu) chemistry on a Symphony multi-peptide synthesizer (Gyros Protein Technologies. Tucson, AZ).

[0336] The resin support consisted of 1% DVB cross-linked polystyrene (H-Pro-2-chlorotrityl resin, 200-400 mesh, Novabiochem) with a degree of substitution of 0.6 mmol / g. Standard side chain protecting groups were used. Fmoc-Lys(Alloc)-OH was used for lysine residues at position 20 and Boc-Tyr(tBu)-OH was used for tyrosine residues at position 1. The Fmoc group was removed using 20% ​​piperidine in DMF before each coupling step (2x10 min). All standard amino acid couplings were performed for 1 hour using equimolar ratios of Fmoc amino acids (0.3 M in DMF), diisopropylcarbodiimide (0.9 M in DCM) and Oxyma (0.9 M in DCM) at a 9-fold molar excess of the theoretical peptide loading. The exception was the coupling with Cα-methylated amino acids, which was coupled for 3 hours. After the synthesis of the peptide backbone was completed, the resin was washed thoroughly with DCM to remove residual DMF. The Alloc protecting group on the lysine residue at position 20 was selectively removed from the peptide resin by treatment with tetrakis(triphenylphosphine)palladium(0) (2-fold molar excess) and phenylsilane (30-fold molar excess) in DCM (3x30 min treatment), and the resin was washed thoroughly with sodium diethyldithiocarbamate (10% w / w in DMF, 3x5 min), followed by thorough washing with DCM and DMF.

[0337] Subsequently, the attachment of the linker moiety was accomplished by stepwise coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.) and Fmoc-glutamic acid α-tert-butyl ester (Fmoc-L-Glu-OtBu, Ark Pharm, Inc.) following the standard coupling and deprotection reactions described above. After removal of the last Fmoc protecting group, mono-OtBu-eicosanedioic acid (WuXi AppTec, Shanghai, China) was coupled overnight using a 4-fold excess of fatty acid, diisopropylcarbodiimide, and Oxyma (1:1:1 mol / mol / mol) in a 1:1 DCM / DMF solution. After the synthesis was complete, the peptide resin was washed with DCM and then thoroughly dried under vacuum.

[0338] The dried resin was treated with 10mL cleavage mixture (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5v / v) at room temperature for 2 hours. The resin was filtered out, washed twice with 2mL pure T'FA, and the combined filtrate was treated with 5 times excess volume of cold ether (-20°C) to precipitate the crude peptide. The peptide / ether suspension was then centrifuged at 3500rpm for 2min to form a solid precipitate, the supernatant was decanted, and the solid precipitate was ground again with ether twice and dried in a vacuum. The crude peptide was dissolved in 20mL 20% acetonitrile / 20% acetic acid / 60% water, and purified by RP-HPLC with a linear gradient of 100% acetonitrile and 0.1% TFA / water buffer system on a SymmetryPrep 7μm C18 preparative column (19x 300mm, Waters). The purity of the peptide was assessed using analytical RP-HPLC, with a combined standard of >95%. The final main product pool was then lyophilized to give the lyophilized peptide TFA salt. The main pool of Example 1 was found to be 96.0% pure. The molecular weight was determined by LC-MS (observed: M+3=1378.7; calculated M+3=1378.9).

[0339] Determination

[0340] Conditions and data for several example assays are provided below. The assays provided support in vitro functionality and selectivity, immunogenicity analysis, pharmacokinetics, and in vivo type 2 diabetes models.

[0341] Binding assay

[0342] Glucagon (abbreviated as Gcg) is a reference standard prepared by Eli Lilly and Company. GLP-1,7-36-NH2 (referred to as GLP-1) was obtained from CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 μM aliquots in 100% DMSO). GIP 1-42 (referred to as GIP) was prepared at Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above (>80% purity, 100 μM aliquots in 100% DMSO). 125 I]-Radiolabeled Gcg, GLP-1 or GIP using [ 125 I] -Lactoperoxidase preparation obtained from Perkin Elmer (Boston, MA).

[0343] Stably transfected cell lines were prepared by subcloning the receptor cDNA into the pcDNA3 expression plasmid and transfected into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese Hamster Ovary (CHO) (hGIPR) cells, followed by selection with Geneticin (hGLP-1R and hGIPR) or hygromycin B (hGcgR).

[0344] Two methods were used to prepare crude cell membranes.

[0345] Method 1 : The frozen cell pellet was incubated in 50 mM Tris HCl, pH 7.5 and Roche Complete TM Lyse on ice in a hypotonic buffer containing EDTA and protease inhibitors. The cell suspension was broken up by grinding 25 times with a glass Potter-Elvehjem homogenizer with a pestle. The homogenate was centrifuged at 1100 x g for about 10 min at about 4°C. The supernatant was collected and stored on ice while the pellet was resuspended in homogenization buffer and rehomogenized as described above. The homogenate was centrifuged at about 1100 x g for about 10 minutes. The second supernatant was combined with the first supernatant and centrifuged at about 35,000 x g for about 1 hour at about 4°C. The resulting membrane pellet was resuspended in homogenization buffer containing about 1 to 3 mg / mL protease inhibitors, snap frozen in liquid nitrogen, and stored in aliquots in a -80°C freezer until use.

[0346] Method 2 : The frozen cell pellet was placed in a 50 mM Tris HCl pH 7.5, 1 mM MgCl2, Roche Complete TMCells were lysed on ice in hypotonic buffer containing EDTA-free protease inhibitors and 25 units / ml DNAse I (Invitrogen). The cell suspension was broken up by grinding 20 to 25 times with a glass Potter-Elvehjem homogenizer with a pestle. The homogenate was centrifuged at about 1800 x g for about 15 minutes at about 4 ° C. The supernatant was collected and stored on ice, and the pellet was resuspended in a homogenization buffer (without DNAse I) and re-homogenized as described above. The homogenate was centrifuged at about 1800 x g for about 15 minutes. The second supernatant was combined with the first supernatant and centrifuged at about 1800 x g for about 15 minutes. The total supernatant was then centrifuged at about 25000 x g at about 4 ° C for about 30 minutes. The resulting membrane pellet was resuspended in a homogenization buffer (without DNAse I) containing about 1 to 3 mg / mL protease inhibitors and stored in a -80 ° C refrigerator in aliquots until use.

[0347] Binding assay

[0348] because[ 125 I] The propanol content of the starting material was high, so the equilibrium binding dissociation constants (K) for various receptor / radioligand interactions were determined by homologous competition binding assays rather than saturation binding. d ). K of receptor preparation d Values ​​were determined as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0349] [ 125 I]-glucagon binding

[0350] The human Gcg receptor binding assay was performed using the Scintillation Proximity Assay (SPA) format using wheat germ agglutinin (WGA) beads (Perkin Elmer). The binding buffer contained 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin (Research Products), 0.003% (w / v) polyoxyethylene sorbitan monolaurate, and 1% (w / v) dapoxetine. and RocheComplete TM EDTA-free protease inhibitors. Peptides and Gcg were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of the serially diluted compound or DMSO was transferred to 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, final concentration 1 μM). Then, 50 μL of [ 125 I]-Gcg (final concentration 0.15 nM), 50 μL human GcgR membrane (1.5 μg / well) and 50 μL WGA SPA beads (80 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute. After incubation / sedimentation at room temperature for about 12 hours, the plate was stirred using a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for peptides tested in the reaction curves was typically 1150 nM to 0.058 nM, while the final assay concentration range for control Gcg was 1000 nM to 0.05 nM.

[0351] [ 125 I]-GLP-1 binding

[0352] The human GLP-1 receptor binding assay was performed in a SPA format using WGA beads. The binding buffer contained 25 mM HEPES pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) and RocheComplete TM EDTA-free protease inhibitors. Peptides and GLP-1 were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of the serially diluted compound or DMSO was transferred to 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, final concentration 0.25 μM). Then, 50 μL of [ 125 I]-GLP-1 (final concentration 0.15 nM), 50 μL human GLP-1R membrane (0.5 μg / well) and 50 μL WGASPA beads (100 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and incubated / sedimented at room temperature for 5 to 12 hours using a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for peptides tested in the reaction curves was typically 1150 nM to 0.058 nM, while the final assay concentration range for control GLP-1 was 250 nM to 0.013 nM.

[0353] [ 125 I]-GIP binding

[0354] The human GIP receptor binding assay was performed in a SPA format using WGA beads. The binding buffer contained 25 mM HEPES pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) and RocheComplete TM EDTA-free protease inhibitors. Peptides and GIP were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of the serially diluted compound or DMSO was transferred to 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled GIP control (nonspecific binding or NSB, final concentration 0.25 μM). Then, 50 μL of [ 125 I]-GIP (final concentration 0.075-0.15 nM), 50 μL human GIPR membrane (3 μg / well) and 50 μL WGA SPA beads (100 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute, then incubated / sedimented at room temperature for 2.5 to 12 hours before using a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for peptides tested in the reaction curves was typically 1150 to 0.058 nM or 115 nM to 0.0058 nM, while the final assay concentration range for the control GIP was 250 nM to 0.013 nM.

[0355] Binding assay data analysis

[0356] Raw CPM data for peptide, Gcg, GLP-1, or GIP concentration curves were converted to percent inhibition by subtracting nonspecific binding (binding in the presence of excess unlabeled Gcg, GLP-1, or GIP, respectively) from the individual CPM values ​​and dividing by the total binding signal (also corrected by subtracting nonspecific binding). 50 Data were analyzed using the nonlinear regression program (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland). Affinity constant (K i ) is based on the equation K i =IC 50 / (1+D / K d )From the absolute IC 50 The value is calculated as, where D is the concentration of radioligand used in the experiment, and IC 50is the concentration that causes 50% inhibition of binding, K d is the equilibrium binding dissociation constant of the radioligand (as described above). i Values ​​are expressed as geometric means, with errors expressed as standard error of the mean (SEM), with n equal to the number of independent replicates (determined in assays performed on different days). The geometric mean was calculated as follows:

[0357] Geometric mean = 10 (arithmetic mean of LogKi values)

[0358] n = 1 / x means that only one value out of the total number of replicates (x) is used to represent the mean. SEM is calculated only when there are n = 2 or more unqualified results. Means are presented as geometric means with the standard error of the mean (SEM) and number of replicates (n) in parentheses.

[0359] Table 1. In vitro binding affinities (K) of the examples and comparative molecules to human GLP-1R, GcgR and GIPR i ).

[0360] Binding affinity

[0361]

[0362] In vitro binding data support selective GIP / GLP-1 receptor binding of the example compounds.

[0363] Functional hGIP-R, hGLP-1R and hGCGR assays

[0364] Methods: Functional activity was determined using cAMP formation in HEK-293 clonal cell lines expressing hGIPR, hGLP-1R or hGCGR. Cells expressing hGIPR, hGLP-1R or hGCGR receptors were treated with control peptide or one of the examples (20 point concentration response curve, 2.75x Labcyte Echo direct dilution in DMSO, 384-well plate Corning Cat#3570) in DMEM (Gibco Cat#31053) supplemented with 1X GlutaMAX TM (Gibco Cat#35050), 0.1% bovine casein (Sigma C4765-10ML), 250 μM IBMX (3-isobutyl-1-methylxanthine, Acros Cat#228420010) and 20 mM HEPES (Gibco Cat#15630). Experiments with the addition of 1.0% fatty acid-free, globulin-free human serum albumin (Sigma Cat#A3782) were also performed under essentially the same assay conditions.

[0365] After incubation at 37°C for 30 minutes, the resulting increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2HTRF Assay Kit (62AM4PEJ). Briefly, the cells were lysed by adding cAMP-d2 conjugate in cell lysis buffer (10 μL), followed by the addition of antibody anti-cAMP-Eu in cell lysis buffer (10 μL). 3+ -Cryptate was used to detect intracellular cAMP levels. The resulting competitive assay was incubated at room temperature for at least 60 min and then analyzed using a PerkinElmer The instrument was detected with an excitation wavelength of 320 nm and emission wavelengths of 665 nm and 620 nm. The Envision unit (emission wavelength of 665 nm / 620 nm*10,000) is inversely proportional to the amount of cAMP present and is converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP produced in each well (nM) was converted to a percentage of the maximum response observed for human GIP(1-42)NH2, hGLP-1(7-36)NH2, or hGCG. The relative EC values ​​were obtained by nonlinear regression analysis, using the percentage of maximum response vs. the added peptide concentration, and fitting to a four-parameter logistic equation. 50 Value and percentile top(E max ).

[0366] Results: Functional data for hGIP(1-42)NH2, hGLP-1(7-36)NH2, hGCG and example compounds are provided in Table 2 (0.1% bovine casein) and Table 3 (0.1% bovine casein, 1.0% human serum albumin) below.

[0367] Table 2: Functional cAMP potency (EC) of peptides incubated at 37°C in the presence of 0.1% bovine casein 50 ) and efficacy (E max )

[0368]

[0369] ND = Not Determined

[0370] a Density is expressed using [ 125 I] GLP-1(736)NH2 at hGLP-1R (112 fmol / mg protein), [ 125 I]GCG at hGCGR (98 fmol / mg protein) and [ 125 The homologous competitive binding of I]GIP(1-42) at hGIPR (124 fmol / mg protein) was determined.

[0371] b EC 50 , nM = geometric mean, followed by standard error of the mean and number of observations in parentheses.

[0372] c Emax, % = arithmetic mean ± standard error of the mean of the maximum response percentage of GLP-1(7-36)NH2 at hGLP-1R, GCG at hGCGR or GIP(1-42)NH2 at hGIPR.

[0373] All values ​​shown are to three significant figures.

[0374] Table 3: Functional cAMP potency (EC) of peptides incubated at 37°C in the presence of 0.1% bovine casein and 1.0% human serum albumin 50 ) and efficacy (E max )

[0375]

[0376] ND = Not Determined

[0377] a Density is expressed using [ 125 I] GLP-1(736)NH2 at hGLP-1R (112 fmol / mg protein), [ 125 I]GCG at hGCGR (98 fmol / mg protein) and [ 125 The homologous competitive binding of I]GIP(1-42) at hGIPR (124 fmol / mg protein) was determined.

[0378] b EC 50 , nM = geometric mean, followed by standard error of the mean and number of observations in parentheses.

[0379] c Emax, % = arithmetic mean ± standard error of the mean of the maximum response percentage of GLP-1(7-36)NH2 at hGLP-1R, GCG at hGCGR or GIP(1-42)NH2 at hGIPR.

[0380] All values ​​shown are to three significant figures.

[0381] In vivo studies

[0382] Pharmacokinetics in male CD-1 mice

[0383] The pharmacokinetics of the test peptides were evaluated after a single subcutaneous administration of 200 nMol / kg to male CD-1 mice. Blood samples were collected over 168 hours and the resulting individual plasma concentrations were used to calculate pharmacokinetic parameters. Plasma (K3EDTA) concentrations were determined using a qualified LC / MS method that measures the intact mass of the test peptide. Each test peptide and the analog as an internal standard were extracted from 100% mouse plasma using an immunoaffinity-based anti-GIP / GLP1 antibody precipitation method. The instrument combination was used for LC / MS detection. Average pharmacokinetic parameters determined whether the test peptide was consistent with an extended pharmacokinetic profile.

[0384] Insulin secretion in male Wistar rats

[0385] Male Wistar rats (280-320 g) with femoral artery and femoral vein catheters (Envigo, Indianapolis, IN) were housed individually in polycarbonate cages with filter tops. Rats were maintained at 21°C, 12:12 h light-dark cycle (lights on at 6:00 A.M.), and received food and deionized water ad libitum. Rats were randomized by body weight and administered 1.5 ml / kg subcutaneously at 0.04, 0.1, 0.3, 1, 3, and 10 nmol / kg of test peptide doses 16 hours before glucose administration, followed by fasting. Animals were weighed and anesthetized with sodium pentobarbital (65 mg / kg, 30 mg / ml) intraperitoneally. At time 0, blood samples were collected in EDTA tubes, and then glucose (0.5 mg / kg, 5 ml / kg) was administered intravenously. Blood samples were collected at 2, 4, 6, 10, 20, and 30 min after intravenous glucose administration to determine glucose and insulin levels. Plasma glucose levels were determined using a clinical chemistry analyzer. Plasma insulin was determined using an electrochemiluminescence assay (Meso Scale, Gaithersburg, MD). n = 5 animals per group, glucose and insulin AUC compared to vehicle controls were examined. Results are given (SEM) (N). The results show the effect of the test peptides on insulin secretion during the intravenous glucose tolerance test. The results show that the test peptides have a dose-dependent effect on insulin secretion.

[0386] Diet-induced obesity in C57 / B16 mice

[0387] C57 / Bl6 diet-induced obese (DIO) male mice weighing 41-50 g were used (Taconic, Germantown, NY). Animals were housed individually in a temperature-controlled (24°C) facility with a 12-hour light-dark cycle (lights off at 10:00 AM and lights on at 10:00 PM) with free access to food and water. After acclimating to the facility for 2 weeks, mice were randomly assigned to treatment groups (n=6 / group) based on body weight, so that the starting average body weight of each group was similar.

[0388] Mice were treated with vehicle (40 mM Tris-HCl, pH 8.0) or test peptides at doses ranging from about 0.03 nmol / kg to about 10 nmol / kg. Subcutaneous administration was performed daily (QD) to ad libitum fed DIO mice 30-90 minutes before the onset of the dark cycle for 14 days. Body weight and food intake were monitored daily.

[0389] Data are presented as mean ± SEM of 5-6 rats per group. Statistical analysis was assessed by one-tailed ANOV followed by Dunnett's multiple comparison test to compare treatment groups with the vehicle group or each other. Significant differences were determined at p < 0.05.

[0390] Weight percentage = Body weight after 14 days of treatment x 100

[0391] Weight before treatment

[0392] The "0" dose group represents mice that received vehicle treatment during each study. All data are expressed as mean ± SEM of 5-6 mice per group. "Δ relative to vehicle" refers to the difference in body weight between the test group and the vehicle group on day 15. "% change" refers to the percent weight loss between day 1 and day 15 in the test group. The percent weight loss of animals receiving vehicle treatment was recorded. For peptides that tested positive in the assay, the Δ relative to vehicle and % change data were statistically significantly different from the control (p<0.05).

[0393] Amino acid sequence

[0394] SEQ ID NO: 1 (human GIP)

[0395] YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-NH2

[0396] SEQ ID NO:2 (human GLP-1)

[0397] HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

[0398] SEQ ID NO:3

[0399] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0400] wherein X1 is Aib; X2 is Aib; K at position 20 is obtained by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) with 18 -CO2H was chemically modified by coupling with the ε-amino group of the K side chain; and the C-terminal amino acid was amidated to form a C-terminal primary amide.

[0401] SEQ ID NO:4 (human glucagon)

[0402] HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

[0403] SEQ ID NO:5

[0404] GPSSG

[0405] SEQ ID NO:6

[0406] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0407] SEQ ID NO:7

[0408] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0409] SEQ ID NO:8

[0410] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18-CO2H)-AFVQWLIAGG-NH2

[0411] SEQ ID NO:9

[0412] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH

[0413] SEQ ID NO:10

[0414] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2

[0415] SEQ ID NO:11

[0416] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-OH

[0417] SEQ ID NO:12

[0418] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH

[0419] SEQ ID NO:13

[0420] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0421] SEQ ID NO:14

[0422] Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30

[0423] SEQ ID NO:15

[0424] GPSSG-NH2

Claims

1. A pharmaceutical composition comprising a compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b- CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G, GP and GPSSG; a is 1 or 2; b is 1 or 2; c is 16 or 18; The C-terminal amino acid is optionally amidated to a C-terminal primary amide (SEQ ID NO: 6); or or pharmaceutically acceptable salts thereof.

2. A composition as claimed in claim 1, wherein c is 18.

3. A composition as claimed in claim 1 or claim 2, comprising a compound selected from the group consisting of: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-NH2; Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH; Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2; Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-OH; and Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH, or or pharmaceutically acceptable salts thereof.

4. A composition as claimed in claim 1, comprising the compound Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH; or a pharmaceutically acceptable salt thereof.

5. A composition as claimed in claim 1, comprising a compound of the formula: or a pharmaceutically acceptable salt thereof.

6. A composition as claimed in any one of claims 1 to 5, further comprising at least one pharmaceutically acceptable excipient.

7. A method for treating type 2 diabetes in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

8. A method for treating type 2 diabetes in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6, in combination simultaneously, separately or sequentially with one or more active agents selected from the group consisting of GIP / GLP1 agonists, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors and sodium glucose cotransporters.

9. A method as claimed in claim 8, wherein the GIP / GLP1 agonist is telpotide or a pharmaceutically acceptable salt thereof.

10. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

11. A method for long-term weight management in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

12. A method for inhibiting weight gain in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

13. A method for reducing body weight in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

14. A method for improving glycemic control in a patient in need thereof, comprising administering an effective amount of a composition as claimed in any one of claims 1 to 6.

15. Compound of the following formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G, GP and GPSSG; a is 1 or 2; b is 1 or 2; c is 16 or 18; The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Its pharmaceutically acceptable salts; for use in therapy.

16. Compound of the following formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G, GP and GPSSG; a is 1 or 2; b is 1 or 2; c is 16 or 18; The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Its pharmaceutically acceptable salt is used in a composition for treating type 2 diabetes.

17. Compound of the following formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G, GP and GPSSG; a is 1 or 2; b is 1 or 2; c is 16 or 18; The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or Its pharmaceutically acceptable salt; for improving long-term weight management.

18. Compound of the following formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H)-AX 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G-NH2, G-OH, GP-OH, GPSSG-NH2 (SEQ ID NO: 15) and GPSSG-OH (SEQ ID NO: 5); a is 1 or 2; b is 1 or 2; c is 16 or 18; The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or or pharmaceutically acceptable salts thereof.

19. A composition as claimed in claim 18, wherein c is 18.

20. A compound as claimed in claim 18 or 19, wherein the compound is selected from the group consisting of: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-NH2 Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-NH2 Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGG-OH Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-NH2 Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGPSSG-OH; and Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)-AFVQWLIAGGP-OH; or or pharmaceutically acceptable salts thereof.

21. The compound of the formula: Y-Aib-EGTFTSDYSI-Aib-LDKIAQ-K-A-X 22 -VQWLIAG-X 30 in X 22 is F or 1-Nal; X 30 Selected from G, GP and GPSSG; and The C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof.

22. A compound as claimed in claim 21, wherein X 30 is GP; or a pharmaceutically acceptable salt thereof.

23. A compound as claimed in claim 22 wherein at least one hydrogen is deuterated to contain greater than 0.015% deuterium.

24. A composition comprising a compound as claimed in any one of claims 21 to 23.

25. A composition as claimed in claim 24, comprising at least one pharmaceutically acceptable excipient.

26. A method for treating type 2 diabetes in a patient in need thereof, comprising administering an effective amount of a compound as claimed in any one of claims 21 to 23, or a pharmaceutically acceptable salt thereof.

27. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of a compound as claimed in any one of claims 21 to 23, or a pharmaceutically acceptable salt thereof.

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