EP4294423A1 - Gip/glp1 dual agonist therapeutic methods - Google Patents

Gip/glp1 dual agonist therapeutic methods

Info

Publication number
EP4294423A1
EP4294423A1 EP22706153.8A EP22706153A EP4294423A1 EP 4294423 A1 EP4294423 A1 EP 4294423A1 EP 22706153 A EP22706153 A EP 22706153A EP 4294423 A1 EP4294423 A1 EP 4294423A1
Authority
EP
European Patent Office
Prior art keywords
ethoxy
group
glu
amino
acetyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22706153.8A
Other languages
German (de)
French (fr)
Inventor
Laura FERNANDEZ LANDO
Angel RODRIGUEZ BERNARDINO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP4294423A1 publication Critical patent/EP4294423A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the field of medicine.
  • treatment methods for refractor ⁇ ' type 2 diabetes (T2D) in patients failing to reach recommended glucose targets with metformin and SGLT-2 treatment are provided.
  • methods relating to increasing HDL-C levels in a patient in need thereof are provided.
  • methods for lowering blood pressure in a patient in need thereof are provided.
  • HbAlc Glycated hemoglobin
  • ADA American Diabetes Association
  • HbAlc Glycated hemoglobin
  • ADA American Diabetes Association
  • a patient with HbAlc less than or equal to 5.7% is considered normal glycemia.
  • Patient treatment goals for HbAlc may vary by patient; however, persistently poorly controlled HbAlc contributes disproportionately to the development of complications associated with diabetes.
  • Patients with type 2 diabetes often fail to achieve normal glycemia despite treatment using the ADA treatment paradigm.
  • the ADA guidelines suggest a reasonable HbAlc treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin.
  • Refractory type 2 diabetes is generally explained by an insulin secretory defect, or beta cell damage, becoming more and more profound with time, against a background of (relatively stable) insulin resistance. Patients living with type 2 diabetes for at least 8 years are more is likely to suffer from refractory type 2 diabetes. Therefore, there is a desire for a treatment method providing normal, or near normal glycemia, in a patient with refractory type 2 diabetes. There is a desire for a treatment method providing normal, or near normal glycemia, in a patient with refractory type 2 diabetes, wherein the patient has been treated for type 2 diabetes at least 8 years.
  • High blood pressure is a risk factor for stroke, coronary heart disease (CHD), and other significant health threats.
  • CHD coronary heart disease
  • Many patients with type 2 diabetes and obesity experience high blood pressure; however, approved treatments for diabetes typically have little or no effect on controlling high blood pressure.
  • treatment options There is a desire for treatment options to manage high blood pressure.
  • Low serum levels of high-density lipoprotein cholesterol (HDL-C) is another known risk factor for coronary heart disease (CHD).
  • CHD coronary heart disease
  • Patients with type 2 diabetes often experience low serum levels of HDL-C; however, approved diabetes treatments generally fail to raise HDL-C.
  • HDL-C is inversely and independently associated with the risk of developing CHD.
  • a drug therapy to increase HDL-C levels.
  • a treatment method to raise HDL-C in a patient with type 2 diabetes.
  • the present invention provides methods for treating, preventing, or delaying high blood pressure, comprising administering a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof.
  • the present invention further provides methods for treating, preventing, or delaying high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods for treating, preventing, or delaying low HDL-C, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
  • the preset invention further provides methods for treating, preventing, or delaying HDL-C in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods for treating, preventing, or delaying refractory type 2 diabetes in a patient having type 2 diabetes for at least 8 years, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof
  • the present invention provides methods for treating refractory type 2 diabetes in a patient having type 2 diabetes for at least 8 years, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
  • the patient in need of treatment for refractory type 2 diabetes has an HbA1c of greater than 10%.
  • the patient in need of treatment for refractory type 2 diabetes has an HbA1c of greater than 11%.
  • the patient in need of treatment for refractory' type 2 diabetes has an HbAlc treatment goal of 5.7%. In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbAlc treatment goal of less than or equal to 5.7%. In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbA1c treatment goal of 6%.
  • the patient in need of treatment for refractory type 2 diabetes has an HbA1c treatment goal of 7%.
  • the present invention provides methods for treating refractory type 2 diabetes in a patient who is non-responsive to metformin, SGLT-2 or metformin plus an SGLT-2 inhibitor, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof.
  • an embodiment provides a method for treating, preventing, or delaying high blood pressure in a patient in need thereof, compri sing administering an effective amount of a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • a further embodiment provides a method for treating high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering an effective amount of a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the present invention provides a method of preventing or delaying high blood pressure in a patient, comprising administering a GIP/GLPl agonist in a therapeutically effective amount to the patient once weekly.
  • the present invention provides a method of preventing or delaying high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist in a therapeutically effective amount to the patient once weekly.
  • the present invention provides use of a GIP/GLPl agonist for the preparation of a medicament for treating, preventing or delaying development of high blood pressure in a patient, wherein the medicament is administered once weekly.
  • the present invention provides methods for treating, preventing or delaying high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptabl e salt thereof to a patient in need of such treatment.
  • the patient in need of treatment for high blood pressure has type 2 diabetes and is non-obese.
  • the patient in need of treatment for high blood pressure has type 2 diabetes and obesity. In an embodiment, the patient in need of treatment for high blood pressure has refractory type 2 diabetes.
  • the patient in need of treatment for high blood pressure has type 2 diabetes for at least 8 years.
  • an embodiment provides a method of treating, preventing or delaying development of hypertensive crisis in a patient with refractory type 2 diabetes, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the patient in need of treatment for hypertensive crisis has type 2 diabetes and is non-obese.
  • the patient in need of treatment for hypertensive crisis has type 2 diabetes and obesity.
  • the patient in need of treatment for hypertensive crisis has refractory type 2 diabetes.
  • the patient in need of treatment for hypertensive crisis has type 2 diabetes for at least 8 years.
  • an embodiment provides a method of treating, preventing or delaying development of low HDL-C in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the present invention provides a method of preventing or delaying hypertensive crisis in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the present invention provides a method of preventing or delaying low HDL-C in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the present invention provides a method of treating high blood pressure in a patient receiving clinical treatment for type 2 diabetes using oral anti diabetic agents for at least 1 year, 2 years, 3, year, 4 year or 5 years wherein the patient’s HbA1c is > 7%, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
  • the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
  • the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly for at least 30 weeks, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
  • the present invention provides a method of improving weight management in a patient with obesity and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
  • the present invention provides a method for treating high blood pressure in patient, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the patient’s weight is within a normal weight range for the patient.
  • the present invention provides a method of improving weight management in a patient with obesity and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing high blood pressure.
  • a GIP/GLPl agonist for use in treating, preventing or delaying development of hypertensive crisis wherein the GIP/GLPl agonist is administered once weekly.
  • a method provides a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in treating, preventing or delaying development of high blood pressure wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered once weekly.
  • an embodiment is the use of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating, preventing or delaying development of high blood pressure, wherein the medicament is administered once weekly.
  • a GIP/GLP1 agonist for the preparation of a medicament for treating, preventing or delaying development of high blood pressure, wherein the medicament is administered once weekly.
  • an embodiment is the use of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating, preventing or delaying development of hypertensive crisis, wherein the medicament is administered once weekly.
  • a GIP/GLP1 agonist for the preparation of a medicament for treating, preventing or delaying development of hypertensive crisis, wherein the medicament is administered once weekly.
  • the GIP/GLP1 agonist is described and claimed in W02020/023386 (Eli Lilly).
  • hypertensive crisis means blood pressure is dangerously high and may threaten patient organs or life. Hypertensive crisis is typically blood pressure that is at least 180/120. High blood pressure is generally 130/80 systolic/diastolic pressure.
  • refractory type 2 diabetes refers to a patient unable to achieve their HbA1c goal using oral standard of care medications, such as metformin.
  • HbA1c goal means the desired average HbA1c level to be achieved by the patient, as determined by the patient’s clinical treatment plan, and as measured using clinically accepted methods.
  • Current ADA guidelines suggest a reasonable HbA1c treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin.
  • the HbA1c goal is 7% or less.
  • the HbA1c goal is 5.7% or less.
  • VA-HIT Veterans Administration HDL Intervention Trial
  • treatment are meant to include slowing or attenuating the progression of a disease, condition or disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if progression of the disorder or condition is not itself slowed or reversed.
  • prevent prevent
  • prevention prevention
  • avoidance of the onset of a disease, condition, disorder or symptom are meant to include avoidance of the onset of a disease, condition, disorder or symptom.
  • the terms “delay,” “delaying,” and the like are meant to include increasing the duration of time that occurs until onset of a disease, condition, disorder or symptom.
  • the term “composite” refers to the first to occur of any of the outcomes.
  • the term “increase HDL-C” means the measured HDL-C level increases from baseline. In an embodiment, increase HDL-C change is statistically significant increase. In an embodiment, increase HDL-C is greater than 2% increase from baseline. In an embodiment, increase HDL-C is greater than 5% increase from baseline. In an embodiment, increase HDL-C is greater than 7% increase from baseline. In an embodiment, increase HDL-C is greater than 10% increase from baseline.
  • “Therapeutically effective amount” means the amount of GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the methods and uses of the present invention, or pharmaceutical composition comprising a GIP/GLP agonist, or a pharmaceutically acceptable salt thereof, for the methods and uses of the present invention, that will elicit the biological or medical response of or desired therapeutic effect on the patient that is being sought by the researcher, medical doctor, or other clinician.
  • An effective amount of GIP/GLP 1 agonist, or a pharmaceutically acceptable salt thereof may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of GIP/GLP 1 agonist to elicit a desired response in the individual.
  • an effective amount is also one in which any toxic or detrimental effect is outweighed by the therapeutically beneficial effects.
  • the therapeutically effective amount of a GIP/GLP 1 agonist for use in the methods described herein is administered as an oral dosage form.
  • the therapeutically effective amount of a GIP/GLP 1 agonist is administered once per day.
  • the therapeutically effective amount of a GIP/GLP] agonist is administered twice per day.
  • the therapeutically effective amount of a GIP/GLP 1 agonist is administered daily as an oral formulation.
  • a method of improving glycemic control and increasing HDL- C, in a patient with type 2 diabetes mellitus comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly for at least 30 weeks.
  • a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof is administered for at least 40 weeks.
  • a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof is administered for at least 52 weeks.
  • a method of treating, preventing or delaying development of high blood pressure in a patient comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
  • the high blood pressure is selected from the group consisting of high blood pressure and hypertensive crisis.
  • a method of preventing or delaying high blood pressure in a patient comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
  • a method of preventing or delaying high blood pressure in a patient comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient in an oral dosage form.
  • a method of improving glycemic control and treating, preventing or delaying high blood pressure in a patient in a patient diagnosed with type 2 diabetes mellitus comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
  • a method of improving glycemic control and treating, preventing or delaying high blood pressure in a patient in a patient diagnosed with type 2 diabetes mellitus comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient in an oral dosage form.
  • the method results in a reduction in the risk of the patient experiencing high blood pressure. In an embodiment, the method results in a reduction in the risk of the patient experiencing hypertensive crisis. In an embodiment, the method results in a reduction in the risk of the patient experiencing clinically low HDL-C.
  • a method of improving glycemic control in a patient with type 2 diabetes mellitus comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly, wherein the method results in a reduction in the risk of the patient experiencing high blood pressure.
  • a method of any of the above embodiments wherein the once weekly administration of a GIP/GLP1 agonist continue for at least 40 weeks.
  • the patient has one or more of: T2DM; high blood pressure; reduced HDL-C; and obesity.
  • the patient has either: multiple cardiovascular risk factors without high blood pressure or clinically significant high blood pressure.
  • the patient has either: multiple cardiovascular risk factors or HbA1c level above 11%.
  • cardiovascular risk factors means risk for cardiovascular disease selected from the group consisting of: current tobacco use (any form of tobacco); use of at least 1 approved lipid modifying therapy to treat hypercholesterolemia or a documented untreated low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L (100 mg/dL) within the past 6 months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C) ⁇ 1.0 mmol/L (40 mg/dL) for men and ⁇ 1.3 mmol/L (50 mg/dL) for women or triglycerides >2.3 mmol/L (150 mg/dL) within the past 6 months; use of at least 1 blood pressure medication to treat high blood pressure or untreated systolic blood pressure (SBP) >130mm Hg or diastolic blood pressure (DBP) >80 mmHg; measured waist circumference for a male 102 cm; for a female 88 cm.
  • SBP high blood pressure or untreated systolic
  • non-obese means a patient who is not obese by applicable standards.
  • the non-obese patient has body mass index is less than 30 BMI.
  • comorbid means that a patient is diagnosed with having 2 or more medical conditions.
  • the patient’s risk of hypertensive crisis is reduced by at least about 14%. In an embodiment, the patient’s risk of hypertensive crisis is reduced by at least about 10%.
  • the HDL-C levels are increased. In an embodiment, HDL-C levels are increased to a clinically desired level. In an embodiment, is a method of improving glycemic control and increasing HDL-C, in a patient with type 2 diabetes mellitus, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly for at least 30 weeks.
  • the risk of the occurrence of a composite of the following outcomes is reduced: hospitalization for high blood pressure or death.
  • the risk of death or hospitalization for high blood pressure is reduced in a patient treated with an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
  • the risk of the occurrence of a composite of the following outcomes is reduced: high blood pressure and HbA1c above 5.7%. In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL- C, high blood pressure, and HbA1c above 7%.
  • the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1c above 5.7%.
  • the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure, and HbA1c above 6%.
  • a method of reaching normal HbA1c glycemia in a patient with refractory type 2 diabetes comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
  • a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof, is administered using a dose escalation protocol.
  • the patient fails to achieve HbA1c ⁇ 7% using one or two oral diabetes agents for at least one year prior to treatment using a GIP/GLPl agonist, or pharmaceutically acceptable salt thereof.
  • the patient fails to achieve HbA1c ⁇ 8% using one or two oral agents for at least one year prior to treatment using a GIP/GLPl agonist, or pharmaceutically acceptable salt thereof. In an embodiment, the patient fails to achieve HbA1c ⁇ 10% using one or two oral agents for at least one year prior to treatment using a GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof.
  • once weekly GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof administration continues for at least 30 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 40 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 50 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 2 years. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 3 years. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 5 years.
  • the patient was diagnosed with type 2 diabetes at least 8 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
  • the patient was diagnosed with type 2 diabetes at least 10 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
  • the patient was diagnosed with type 2 diabetes at least 13 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is at least 46 years old.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is at least 55 years old.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is at least 60 years old.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin and an SGLT2 oral agent.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered an SGLT2 oral agent.
  • the patient administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof is also administered metformin.
  • the patient administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof is also administered a basal insulin.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin and a basal insulin.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered an SGLT2 and a basal insulin.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin, an SGLT2, and a basal insulin.
  • the basal insulin is insulin glargine.
  • the basal insulin is insulin Degludec.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered an SGLT2 oral pharmaceutical.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin, and 8GLT2 oral, and insulin Degludec.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin, and SGLT2 oral, and insulin Degludec.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin, an SGLT2 oral, and inulin glargine.
  • the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof is also administered metformin and insulin glargine.
  • the present invention provides a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in any of the above embodiments.
  • the present invention provides use of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for any of the above embodiments.
  • the GIP/GLP l agonist is a compound of Formula I: R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (SEQ ID NO:3) wherein:
  • Ri is absent or an Ac modification of the N-terminal amino group
  • Xi is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY;
  • X 2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala ; or Xi and X 2 combine to form desH- ///[NHCO]-Aib;
  • X3 is selected from the group consisting of E, N, Aad, and cTA;
  • X 6 is selected from the group consisting of F, aMeF, and aMeF(2F);
  • X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )qC0 2 H;
  • X 11 is selected from the group consisting of S, aMeS, and D-Ser;
  • X 12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )qC0 2 H;
  • Xi 3 is selected from the group consisting of Me, Aib, L, aMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )qC0 2 H;
  • Xi 4 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
  • Xi 6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-
  • Xi 7 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;
  • X 19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2- [2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X22 is selected from the group consisting of F and aMeF;
  • X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X25 is selected from the group consisting of Y and aMeY;
  • X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )qC0 2 H;
  • X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )q-C0 2 H;
  • X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5) , PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6) , K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 ) q -C0 2 H] X32X33X34-R2 (SEQ ID NO: 7) , K[(2-[2-amino-ethoxy)- ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 ) q -C0 2 H] X32X33X34-R2 (SEQ ID NO: 7) , K[(2-[2-amino-ethoxy)- eth
  • X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )q-C0 2 H];
  • X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO- (CH 2 ) q -C0 2 H];
  • X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )q-C0 2 H];
  • X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl) 2 -(Y-Glu)-CO-(CH 2 )q-C0 2 H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R 2 is absent or a NH 2 modification of the C-terminal group; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R 2 , then X31 is absent; wherein no more than one of X10, Xi 2 , X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X 26 , X 27 , X 28 , X 29 , X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be
  • the GIP/GLP1 agonist is a compound of Formula II, or pharmaceutically acceptable salt thereof, wherein:
  • Xi7 is an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; and X30 is selected from the group consisting of G-R2 and G; wherein if X 30 is G, then X 31 is selected from the group consisting of PX 32 X 33 X 34 - R 2 (SEQ ID NO: 4), wherein X 32 is S, X 33 is S and X 34 is G (SEQ ID NO: 15), and PX32X33X34X35X3 6 X37X3 8 X3 9 -R2 (SEQ ID NO: 5), wherein X32 is S, X33 is S, X 34 is G, X 35 is A, X 36 is P, X 37 is P, X 38 is P and X 39 is S (SEQ ID NO: 16) (hereafter a “Formula III” compound).
  • a compound of Formula III or a pharmaceutically acceptable salt thereof, wherein the Xj ? amino acid is conjugated to the fatty acid via a linker (hereafter a “Formula Ilia” compound).
  • the GIP/GLP1 agonist is a compound of Formula III and Ilia, or a pharmaceutically acceptable salt thereof, wherein:
  • X10 is selected from the group consisting of A, L, H, 3 Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, and cTA;
  • X12 is selected from the group consisting of I, S, and D-Ile;
  • Xi 3 is selected from the group consisting of Me, Aib, L, and aMeL;
  • Xi 4 is selected from the group consisting of L and K;
  • Xi 6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, and R;
  • X 19 is selected from the group consisting of Q, and A;
  • X20 is selected from the group consisting of Aib, Q, H, R, K, and aMeK;
  • X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I;
  • X 23 is selected from the group consisting of I, L, A, G, F, H, E, and V;
  • X 24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P;
  • X26 is selected from the group consisting of L, and aMeL;
  • X 27 is selected from the group consisting of L, and I;
  • X 28 is selected from the group consisting of E, A, S, and D-Glu;
  • X 29 is selected from the group consisting of Aib, G, and A;
  • X 30 is selected from the group consisting of G and G-R 2 ; wherein if X 30 is G; then X 31 is selected from the group consisting of PX 32 X 33 X 34 - R 2 (SEQ ID NO: 4), wherein X 32 is S, X 33 is S and X 34 is G (SEQ ID NO: 15) and PX32X33X34X35X3 6 X37X38X3 9 -R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X 34 is G, X 35 is A, X 36 is P, X 37 is P, X 38 is P and X 39 is S (SEQ ID NO: 16) (hereafter a “Formula Illb” compound).
  • the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
  • Xi 7 is K conjugated to a C 16 -C 22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker.
  • the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
  • Xi Y
  • X 2 is Aib
  • X 3 is E
  • X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;
  • X 11 is S
  • Xi4 is L
  • Xi 6 is selected from the group consisting of K, E, Om, Dab, and Dap;
  • Xi 7 is K conjugated to a C 16 -C 22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;
  • Xi9 is Q
  • X20 is Aib
  • X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;
  • X22 is F
  • X23 is I;
  • X24 is selected from the group consisting of S, Aad, D-Glu, and E;
  • X26 is L
  • X 28 is selected from the group consisting of E and A.
  • the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
  • Xi Y
  • X2 is Aib
  • X 3 is E
  • X 6 is aMeF(2F);
  • Xjo is selected from the group consisting of Y, 4-Pal, and V;
  • Xu is S
  • X 12 is I
  • Xi 3 is selected from the group consisting of L, Aib, and aMeL;
  • Xi4 is L
  • Xi 6 is selected from the group consisting of E, K, and Om;
  • Xu is K conjugated to a C 16 -C 22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker,
  • Xi9 is Q
  • X20 is Aib
  • X 21 is selected from the group consisting of E, A, and T;
  • X22 is F
  • X24 is D-Glu
  • X 25 is selected from the group consisting of Y and ⁇ MeY;
  • X26 is L
  • X29 is G
  • X30 is G
  • X31 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X 36 is P, X37 is P, X 38 is P, X39 is S (SEQ ID NO: 16).
  • the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein X1 ⁇ 2 is Orn, XB is aMeL, and X 25 is Y.
  • the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein C 1 ⁇ 2 is E, Xn is aMeL, and X 25 is Y.
  • the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein X1 ⁇ 2 is E, XB is aMeL, X 10 is Y, and X 25 is aMeY.
  • the GIP/GLPl agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein C 1 ⁇ 2 is Orn, Xj 3 is aMeL, X 10 is 4Pal, and X 25 is Y.
  • the GIP/GLPl agonist is a compound of Formula I selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.
  • the GIP/GLPl agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y, F, and D-Tyr; Xr, is F; and X13 is selected from the group consisting of Aib, L, and aMeL.
  • the GIP/GLPl agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Riis absent; Xi is selected from the group consisting of Y, F, and D-Tyr; Xe is F; X 13 is selected from the group consisting of Aib, L, and aMeL; X 2 is Aib; X 3 is E; X 10 is Y; Xu is S; X 12 is I; X 14 is L; C 1 ⁇ 2 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, and R; X 17 is an amino acid conjugated to a C 16 -C 22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X 19 is Q; X 20 is selected from the group consisting of Aib, Q, H, and K; X 21 is selected from the group consisting of H,
  • the GIP/GLP1 agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y, F, and D-Tyr; Xr, is F; and X 13 is selected from the group consisting of Aib, L, and aMeL; X 28 is A; X 29 G; X 30 is G; X31 is PX 32 X33X34X35X36X37X38X39-R2 (SEQ ID NO:5); X 34 is G; and X 39 is S .
  • the GIP/GLP1 agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y and D-Tyr; and X 13 is aMeL.
  • the GIP/GLP1 agonist is a compound of Formula I selected from the group consisting of SEQ ID NO:21, SEQ ID NO: 22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NQ:25, and SEQ ID NO:26, or a pharmaceutically acceptable salt thereof
  • the GIP/GLP1 agonist is a compound of Formula VI X1X2EGTX6TSDX10X11X12X13LDX16X17AQX20X21X22IX24X25LIX28GX30 (SEQ ID NO:27) wherein
  • Xi is selected from the group consisting of Y and RiY;
  • Ri is an Ac modification of the N-terminal amino group
  • X 6 is selected from the group consisting of ⁇ MeF and aMeF(2F);
  • X 10 is selected from the group consisting of 4Pal, Y, aMeF, aMeF(2F), aMeL, aMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Me, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ 1 ;
  • X 11 is selected from the group consisting of S, aMeS, Aib, G, Dap, Ac5c, and Tie;
  • X 12 is selected from the group consisting of I and KZ 1 ;
  • Xi 3 is selected from the group consisting of aMeL and aMeF;
  • Xi 6 is Orn
  • Xi 7 is selected from the group consisting of Q, I, and KZ 1 ;
  • X 20 is selected from the group consisting of Aib, Orn, 4Pal, aMeF, Ac5c, and Ac6c;
  • X 21 is selected from the group consisting of E, KZ 1 , G, Orn, and 4Pal;
  • X 22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, aMeF(2F), ChA, Bzt, and aMeF;
  • X 24 is selected from the group consisting of D-Glu, E, G, and KZ 1 ;
  • X 25 is selected from the group consisting of Y, aMeY, aMeF, and KZ 1 ;
  • X 28 is selected from the group consisting of E, Orn, and KZ 1 ;
  • X 30 is selected from the group consisting of G, Orn, KZ 1 , K(Z I )R 6 , OrnR 2 , and GR 2 ;
  • R 2 is selected from the group consisting of X 31 , X 3i SSG(SEQ ID NO:28), X 31 SSG-R 3 (SEQ ID NO:29), X 31 SSGX 35 PPPX 39 (SEQ ID NO:30), X31SSGX35PPPX39R3 (SEQ ID NO:31), X31SSGX35PPPX39X40 (SEQ ID NO:32), X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NEE;
  • R 6 is selected from the group consisting of PSSG(SEQ ID NO:34), PSSG-R 3 (SEQ ID NO:35), PSSGX35PPPX39 (SEQ ID NO:36), PS SGX35PPPX39R3 (SEQ ID NO:37), PSSGX35PPPX39X40 (SEQ ID NO:38), P S S GX 35 PPPX39X40R3 (S
  • X 31 is selected from the group consisting of P and KZ 1 ;
  • X 35 is selected from the group consisting of A and Orn;
  • X 39 is selected from the group consisting of S and Orn;
  • X40 is KZ 1 ;
  • R 3 is a modification of the C-terminal group, wherein the modification is NEE; wherein two, and only two, of X10, X12, X 17 , X21, X24, X25, X28, X30, X31, and X40 are KZ 1 or K(ZI)R 6 ;
  • Zi is selected from the group consisting of R 5 and -R 4 R 5 ;
  • R 4 is a linker; and R 5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
  • Xi is selected from the group consisting of Y and RiY;
  • Ri is an Ac modification of the N-terminal amino group
  • X 2 is Aib
  • X 6 is selected from the group consisting of aMeF and aMeF(2F);
  • X 10 is selected from the group consisting of 4Pal, Y, aMeF, aMeF(2F), aMeL, aMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ 1 ;
  • X 11 is selected from the group consisting of Ac5c, S, aMeS, Aib, G, Dap, and Tie;
  • X 12 is selected from the group consisting of I and KZ 1 ;
  • Xi 3 is selected from the group consisting of aMeL and aMeF;
  • Xi6 is Orn;
  • X 17 is selected from the group consisting of Q, I, and KZ 1 ;
  • X 20 is selected from the group consisting of Aib, Orn, 4Pal, aMeF, Ac5c, and Ac6c;
  • X 21 is selected from the group consisting of E, KZ 1 , G, Orn, and 4Pal;
  • X 22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, aMeF(2F), ChA, Bzt, and aMeF;
  • X 24 is selected from the group consisting of D-Glu, E, G, and KZ 1 ;
  • X 25 is selected from the group consisting of Y, aMeY, aMeF, and KZ 1 ;
  • X 28 is selected from the group consisting of E, Orn, and KZ 1 ;
  • X 30 is selected from the group consisting of G, Orn, KZ 1 , and GR 2 ;
  • R 2 is selected from the group consisting of X 3i SSG(SEQ ID NO:28), X 31 SSG-R 3 (SEQ ID NO:29), X31SSGX35PPPX3 9 (SEQ ID NO:30), X 31 S SGX35PPPX39R3 (SEQ ID NO:31), X 31 S S GX 35 PPPX 39 X 40 (SEQ ID NO:32), X 31 SSGX 35 PPPX 39 X 40 R 3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NEE;
  • X 31 is selected from the group consisting of P and KZ 1 ;
  • X 35 is selected from the group consisting of A and Orn;
  • X 39 is selected from the group consisting of S and Orn;
  • X40 is KZ 1 ;
  • R 3 is a modification of the C-terminal group, wherein the modification is NFE; wherein two, and only two, of X1 0 , X12, X 17 , X21, X24, X25, X28, X30, X 31 , and X40 are KZ 1 ;
  • Zi is selected from the group consisting of R 5 and -R 4 R 5 ; and R 4 is a linker;
  • R 5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
  • the GIP/GLP1 agonist is a peptide of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
  • the GIP/GLP1 agonist is a peptide of Formula I, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
  • the GIP/GLP1 agonist is a peptide of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 17 and X 31 are each KZ 1 .
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Xn and X 24 are each KZ 1 .
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X17 and X 21 are each KZ 1 .
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 17 and X 28 are each KZ 1 .
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 17 and X 40 are each KZ 1 . In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 21 and X 40 are each KZ 1 . In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 21 and X 28 are each KZ 1 . In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X 24 and X 28 are each KZ 1 .
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Xi is Y; Xe is aMeF(2F); X 10 is selected from the group consisting of 4Pal, Y, and KZ 1 ; X 17 is selected from the group consisting of S, aMeS, and Aib; X 12 is I; X 13 is aMeL; C 1 ⁇ 2 is Om; X 17 is selected from the group consisting of I and KZ 1 ; X 20 is Aib; X 21 is selected from the group consisting of KZ 1 and E; X 22 is selected from the group consisting of F and aMeF; X 24 is selected from the group consisting of D-Glu and KZ 1 ; X 25 is aMeY; X 28 is selected from the group consisting of E and KZ 1 ; X 30 is selected from the group consisting of G and GIG; R 2 is selected from the group consisting
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl) 2 -(y-Glu)-CO-(CH 2 )i 2 -C0 2 H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) i2- C0 2 H)SSGAPPPS-NH 2 (SEQ ID NO:41),
  • the GIP/GLP1 agonist is a compond wherein the IQ linker is one to two amino acids selected from the group consisting of eK and y-Glu.
  • the IG linker comprises from one to three (2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl) moieties.
  • the GIP/GLP1 agonist is a compound wherein the FG fatty acid moieties are conjugated to a lysine via an IG linker between the lysine and the IG fatty acid.
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the IG linker comprises from zero to four amino acids; and from zero to three (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.
  • the GIP/GLPl agonist is a compound wherein the IG linker comprises from one to three amino acids each independently selected from the group consisting of eK and g-Glu.
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the R 4 linker comprises from one to two amino acids each independently selected from the group consisting of eK and g-Glu.
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two Zi fatty acid moieties wherein each R 5 fatty acid of the Zi moiety is conjugated to different lysines of the peptide via an R 4 linker wherein, the R 4 linker comprises from zero to two g-Glu amino acid residues.
  • the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two Zi fatty acid moieties wherein each R 5 fatty acid of the Zi is conjugated to different lysines of the peptide via an R 4 linker wherein R 4 comprises from one to three amino acids and from one to three (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.
  • the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated to a different lysine of the peptide via an R 4 linker wherein, R 4 comprises from one to three amino acids each independently selected from the group consisting of eK and x-Glu; and from one to three (2-[2-(2-Amino-ethoxy)-ethoxyj- acetyl) moieties attached to the amino acid.
  • the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated to different lysines of the peptide via an R 4 linker wherein R 4 comprises up to three amino acids each independently selected from the group consisting of g-Glu and eK attached to one or two (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.
  • the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated via an R 4 linker, wherein the R 4 linker has the following formula:
  • al is selected from the group consisting of 0, 1, and 2; a2 is selected from the group consisting of 0, 1, and 2; a3 is selected from the group consisting of 0, 1, 2, and 3; bl is 0 or 1; and b2 is 0 or 1.
  • the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated via an R 4 linker wherein Zi is of the formula:
  • a GIP/GLP1 agonist wherein al is 1, a2 is 0, a3 is 2, bl is 0, b2 is 1, and q is 12; and the structure is:
  • the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated via an R 4 linker, wherein the R 4 linker and R 5 fatty acid components have the following formula: group consisting of 7, 8, 10, 11, and 12.
  • the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R 5 fatty acid of the Zi is each conjugated via an R 4 linker, wherein the R 5 fatty acid is selected from the group consisting of -(7-(4- carboxyphenoxy jheptanoyl ) and -(8-(4-carboxyphenoxy)octanoyl).
  • the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R 4 linker, wherein the R5 fatty acid is selected from the group consisting of -(10-(4- carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), and -(4-(4-tert- butylphenyl)butanoyl).
  • the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -CO-(CH2)i4-CH3 , -CO-(CH2)i2-CH3, and -CO-(CH2)IO-CH3 .
  • the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -C0-(CH 2 )i 2 -C0 2 H and -CO-(CH 2 )10-CO 2 H.
  • the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -CO-(CH2) IO - CH 3 and -CO-(CH 2 )i2-CH 3.
  • the GIP/GLPl agonist is a compound wherein a R5 fatty acid is selected from the group consisting of -C0-(CH2)i2-C02H, -CO-(CH2) IO -C02H, -(10-(4- carboxyphenoxy jdecanoyl ), -(4-(4-iodophenyl)butanoyl), -(4-(4 -tert- butylphenyljbutanoyl), -CO-(CH 2 )i4-CH 3, -CO-(CH 2 )i2-CH 3 , -CO-(CH 2 )IO-CH 3, -(7-(4- carboxyphenoxy jheptanoyl ), and -(8-(4-carboxyphenoxy)octanoyl).
  • a R5 fatty acid is selected from the group consisting of -C0-(CH2)i2-C02H, -CO-(CH2) IO -
  • Certain GIP/GLPl agonist compounds are generally effective over a wide dosage range. For example, dosages for once weekly parenteral dosing may fall within the range of 0.05 mg to about 30 mg per person per week.
  • GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which is produced as a 30-amino acid, C-terminal amidated peptide (GLP-I7-36) (SEQ ID NO:2).
  • GIP is a 42 amino acid peptide (SEQ ID NO: 1), which, like GLP-1, is also known as an incretin, and plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose.
  • a GIP/GLPl agonist compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 5 times the GLP1 receptor potency as measured by the casein cAMP assay described herein below, wherein the potency is normalized against native GIP and GLP on the day the assay is run.
  • a GIP/GLPl agonist compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 10 times the GLP1 receptor potency as measured by the casein cAMP assay, wherein the potency is normalized against native GIP and GLP on the day the assay is run.
  • amino acid means both naturally occurring amino acids and unnatural amino acids.
  • L leucine
  • alpha-methyl substituted residues of natural amino acids e.g., a-methyl leucine, or aMeL and a-methyl lysine, or aMeK
  • alpha amino isobutyric acid or “Aib,” “4Pal,” “Ora,” and the like.
  • Ora means ornithine.
  • 4Pa!” means 3-(4-Pyridyl)-L- alanine.
  • aMeF(2F) means alpha-methyl 2-F -phenylalanine.
  • aMeY means alpha methyl tyrosine, alpha methyl lysine, and alpha methyl leucine, respectively.
  • each of “e” and “D-Glu” means D-glutamic acid.
  • each of “D-His” and “h” means D-histidine.
  • each of “D-Tyr” and “y” means D-tyrosine.
  • each of “D-Ser” and “s” means D-serine.
  • each of “D-Ala” and “a” means D-alanine.
  • “aMeF(2F)” means alpha-methyl-F(2F) and alpha-methyl-Phe(2F).
  • “aMeF” means alpha-methyl -F and alpha-methyl -Phe.
  • aMeY means alpha-methyl -Tyr.
  • aMeK means alpha-methyl-Lys.
  • aMeL means alpha-methyl-Leu.
  • aMeS means alpha- methyl-serine and alpha-methyl-Ser.
  • ⁇ MeP means alpha-methyl- proline and alpha-methyl-Pro.
  • desH means desHis.
  • desY means desTyr.
  • AEEA means (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) ;
  • AEEA2 means (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2;
  • AEEA3 means (2-[2- (2-Amino-ethoxy)-ethoxy]-acetyl)3.
  • Alkyl is 6-Aminohexanoyl-; “Aoc” is 8-Aminooctanoyl-;
  • PEG3 is [3-(2-[2-(2-Amino-ethoxy)-ethoxy]-ethoxy)-propanoyl]-;
  • PEG4 is (3-[2-(2- [2-(2-Amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-propanoyl)-;
  • PEG5 is [3-(2-[2-(2-[2-(2-(2-(2- Amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-propanoyl]-;
  • PEG6 is (3-[2-(2- [2-(2-(2-(2-Amino-ethoxy)-ethoxy]-ethoxy]-ethoxy]-propanoyl)-.
  • Tie is tert-Leucine.
  • the terms “activity,” “activatejsj” “activat[ing]” and the like refers to the capacity of a compound, or a pharmaceutically acceptable salt thereof, to bind to and induce a response at the receptor(s), as measured using assays known in the art, such as the in vitro assays described below.
  • the affinity of GIP/GLP1 agonist compounds, or pharmaceutically acceptable salts thereof, for each of the GIP and GLP-1 receptors may be measured using techniques known for measuring receptor binding levels in the art, including, for example those described in the examples below, and is commonly expressed as a Ki value.
  • the activity of the GIP/GLP1 agonist compounds at each of the receptors may also be measured using techniques known in the art, including for example the in vitro activity assays described below, and is commonly expressed as an EC 50 value, which is the concentration of compound causing half-maximal simulation in a dose response curve
  • the GIP/GLP1 agonist is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a potent GIPR/GLP-IR dual agonist that is a partial agonist on the GLP-1R as demonstrated by a Cell Membrane Guanosine 5'- (gamma-thio) Triphosphate-[ 35 S] (GTPyS) Binding Assay, and a partial agonist on the GLP-1R as demonstarted by a P-arrestin-2 recruitment assay.
  • the compound is a potent GIPR/GLP-IR dual agonist that is a partial agonist on the GLP-1R as demonstrated by a Cell Membrane Guanosine 5'- (gamma-thio) Triphosphate-[ 35 S] (GTPyS) Binding Assay, and a partial agonist on the GLP-1R as demonstarted by a P-arrestin-2 recruitment assay.
  • the GIP/GLPl agonist is a compound, or pharmaceutically acceptable salt thereof, wherein the compound stimulates GLP-1R induced activation of Ga s in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate- [ 35 S] (GTPyS) Binding Assay.
  • the GIP/GLP1 agonist is a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate- [ 35 S] (GTPyS) Binding Assay, and 35% or less in the GLP-CHO Cell b- Arrestin. Recruitment Assay.
  • a GIP/GLP1 agonist means a compound showing 35% or less in the GLP-CHO Cell b-Arrestin.
  • the term “effective amount” refers to the amount or dose of a compound of the present invention, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
  • An effective amount can be determined by a person of skill in the art using known techniques and by observing results obtained under analogous circumstances.
  • a number of factors are considered, including, but not limited to: the species of mammal: its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • EDT A means ethylenediaminetetraacetic acid.
  • DMSO means dimethyl sulfoxide.
  • CPM means counts per minute.
  • IBMX 3-isobutyl-l-methylxanthine.
  • LC/MS liquid chromatography/mass spectrometry.
  • HTRF homogeneous time-resolved fluorescence.
  • BSA bovine serum albumin.
  • estimates refers to- efficacy and treatment- regimen - evaluated to determine the efficacy of a GIP/GLP1 agonist due to requirements by certain regulatory agencies.
  • the efficacy estimand is used to evaluate results in people prior to their discontinuation of study drug or initiating rescue therapy for persistent severe hyperglycemia.
  • present invention provides the following:
  • Embodiment 1 A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of refractory type 2 diabetes in a patient, wherein the GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly.
  • Embodiment 2 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of high blood pressure in a patient, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly.
  • Embodiment 3 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in raising HDL-C in a patient, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly.
  • Embodiment 4. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 3, wherein the patient has type 2 diabetes for at least 8 years.
  • Embodiment 5 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 4, wherein the patient HbA1c goal is less than 7%.
  • Embodiment 6 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 5, wherein the patient HbA1c goal is equal to or less than 5.7%.
  • Embodiment 7 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 6, wherein the patient HbA1c is greater than 10%.
  • Embodiment 8 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 7, wherein the patient HbA1c is greater than 11%.
  • Embodiment 9. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 8, wherein the patient age is at least 46 years.
  • Embodiment 10 A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 9, wherein the patient age is at least 60 years old.
  • Embodiment 11 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 10, wherein the patient is taking an SGLT2 inhibitor.
  • Embodiment 12 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 11, wherein the patient is taking metformin.
  • Embodiment 13 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 12, wherein the patient is not administered a basal insulin.
  • Embodiment 14 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 13, wherein the patient fails to reach their HbA1c goal while taking metformin and an SGLT2 inhibitor.
  • Embodiment 15 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 14, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 40 weeks.
  • Embodiment 16 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 15, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 50 weeks.
  • Embodiment 17 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 16, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 2 years.
  • Embodiment 18 A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 17, wherein the patient is non-ob ese.
  • Embodiment 19 A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 18, wherein the patient has comorbid high blood pressure.
  • Embodiment 20 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 19, wherein the patient has comorbid low HDL-C.
  • Embodiment 21 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 17 or 19 to 20, wherein the patient has comorbid obesity.
  • Embodiment 22 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 21, wherein the patient has at least two cardiovascular risk factors.
  • Embodiment 23 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 21, wherein the patient has no cardiovascular risk factors.
  • Embodiment 24 A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 23, wherein the patient has type 2 diabetes for at least 10 years.
  • Example 1 Clinical Trial using a GIP/GLPl Agonist
  • the enrollment criteria set forth in Table 1 below, are designed to include participants who are similar to patients seen within a typical diabetes practice, and include some patient with type 2 diabetes that is refractory to oral treatment. Geriatric patients are included. Study continues for 52 weeks.
  • the study is designed to consist of a screening visit followed by a single-blind 3- week placebo run-in period. Afterwards, patients are randomized to GIP/GLP1 agonist (dosed using an escalation dose protocol) or insulin degludec (standard titration protocol) and followed at approximately monthly intervals. Patients receiving insulin degludec follow standard insulin degludec titration protocol during the study. Study protocol includes blood pressure measurement at each visit and serum lipid profile at study initiation and at 52 weeks using standard clinical methods.
  • the mean dose of insulin degludec at 52 weeks is about 48 units per day.
  • a greater percent of patients randomized to GIP/GLP1 agonist achieve an HbA1c of less than 7 percent, the American Diabetes Association’s recommended target for people with diabetes, or less than 5.7 percent - the level seen in people without diabetes - than patients randomized to insulin degludec.
  • Example 2 Clinical Trial using a GIP/GLP1 agonist
  • the enrollment criteria set forth in Table 2 below, include patients considered refractory to type 2 diabetes oral treatment; however, oral diabetes treatment continues through the study. Study continues for 40 weeks.
  • the study is designed to consist of a screening visit followed by a 3-week run-in period. Afterwards, patients begin a 40-week randomized, double-blind study with a GIP/GLP1 agonist or placebo, as add-on to their previous treatment with insulin glargine with or without metformin. Insulin glargine dose was titrated throughout the study using a validated treat-to-target algorithm’. Patients are followed at approximately weekly intervals, then approximately monthly. Study protocol includes blood pressure measurement at each visit and serum lipid profile at study initiation and at 40 weeks using standard clinical methods.
  • the study shows doses of a GIP/GLPl agonist can be useful for HbA1c reduction and weight reduction from baseline compared to placebo as an add-on to titrated insulin glargine with or without metformin in adults with type 2 diabetes using the clinical trial dosing.
  • Example 3 Clinical Trial using a GIP/GLPl agonist This study is a 4-week multiple ascending dose study investigating the safety and tolerability of the GIP/GLPl agonist of Example 7 administered as 4 once-weekly subcutaneous injections in patients with Type 2 Diabetes compared with placebo. Prespecified safety parameters to be studied include blood pressure.
  • the study includes 4 cohorts for treatment with the GIP/GLPl agonist.
  • Cohorts 1 and 2 receive 4 fixed doses of 0.3 mg or 1 mg, respectively.
  • Cohorts 3 and 4 receive weekly doses in stepwise increments as shown in Table 3.
  • Criteria are established to enroll patients whose glycemic control is not well controlled on diet and exercise or stable dose of metformin. Baseline demographics of patients enrolled are provided below in Table 4.
  • Table 4 Baseline demographics.
  • SEQ ID NO: 10 The structure of SEQ ID NO: 10 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, K17, Aib20, D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:
  • the peptide backbone of Example 4 is synthesized using Fluorenylmetliyloxycarbonyl (Fmoc)/tert-ButyI (t-Bu) chemistry on a Symphony X peptide synthesizer (Gyros Protein Technologies. Arlington, AZ).
  • the resin consists of 1% DVB cross-linked polystyrene (F moc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.3-0.4 meq/g.
  • Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 and Boc-Tyr(tBu) ⁇ OH) was used for the tyrosine at position 1. Fmoc groups are removed prior to each coupling step (2 x 7 minutes) using 20% piperidine in DMF. All standard amino acid couplings are performed for 1 hour to a primary amine and 3 hour to a secondary amine, using an equal molar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoretical peptide loading.
  • the peptide resin is washed with DCM, and then thoroughly air-dried.
  • the dry resin is treated with 10 raL of cleavage cocktail (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5 v/v) for 2 hours at room temperature.
  • the resin is filtered off, washed twice each with 2 rnL of neat T ’ FA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20°C) to precipitate the crude peptide.
  • the peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo.
  • the crude peptide is solubilized in 20% acetonitrile/20%Acetic acid/60%water and purified by RP- HPLC on a Luna 5 ⁇ m Phenyl-Hexyl preparative column (21 x 250 mm, Pbenomenex) with linear gradients of 100% acetonitrile and 0.1% TF A/water buffer system (30-50% acetonitrile in 60 min).
  • the purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%.
  • the main pool purity of compound 1 is found to be 98.0%. Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA sail.
  • SEQ ID NO: 11 The structure of SEQ ID NO: 11 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Ornl6, K17, Aib20 D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 11 is prepared substantially as described by the procedures of Example 4.
  • Example 6 is a compound represented by the following description:
  • SEQ ID NO: 12 The structure of SEQ ID NO: 12 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Ornl6, K17, Aib20, D-Glu24, and Ser39, where the stmctures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 12 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO: 13 The structure of SEQ ID NO: 13 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24 aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 13 is prepared substantially as described by the procedures of Example 4.
  • the molecular weight is determined by LC- MS (obsd: M+3
  • SEQ ID NO: 14 The structure of SEQ ID NO: 14 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Oml 6, K17, Aib20, D-Glu24,aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
  • SEQ ID N0:21 The structure of SEQ ID N0:21 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:21 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO:22 The structure of SEQ ID NO:22 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:22 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO:23 The structure of SEQ ID NO:23 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:23 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO:24 The structure of SEQ ID NO:24 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, Oml6, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:24 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO:25 The structure of SEQ ID NO:25 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, K17, Aib20, aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:25 is prepared substantially as described by the procedures of Example 4.
  • the molecular weight is determined by LC- MS (obsd: M+3
  • SEQ ID NO:26 The structure of SEQ ID NO:26 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, Oml6, K17, Aib20, aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO:26 is prepared substantially as described by the procedures of Example 4.
  • SEQ ID NO:41 The structure of SEQ ID NO:41 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
  • Example 15 The peptide backbone of Example 15 is synthesized using Fluorenylmethyloxycarbonyl (Fmoc)/tert-Butyl (t-Bu) chemistry on a Symphony multiplex peptide synthesizer (Gyros Protein Technologies. Arlington, A Z).
  • the resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.35 mmol/g. Standard side-chain protecting groups were used.
  • Fmoc-Lys(Mtt)-OH is used for the lysine residues at positions 17 and 31, and Boc-Tyr(tBu)-OH was used for the tyrosine residue at position 1.
  • Fmoc groups are removed prior to each coupling step (2 x 7 minutes) using 20% piperidine in DMF.
  • the Mtt protecting groups on the lysine residues at positions 17 and 31 are selectively removed from the peptide resin using 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (3 x 1 hour treatments), and the resin is thoroughly washed with DCM and DMF.
  • linker moieties Sub sequent attachment of the linker moieties is accomplished by stepwise coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.) and Fmoc-glutamic acid a-t-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), following the procedures described above for standard coupling and deprotection reactions.
  • Fmoc-AEEA-OH 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid
  • Fmoc-Glu-OtBu Fmoc-Glu-OtBu
  • the resin is filtered off, washed twice each with 2 mL of neat TFA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20°C) to precipitate the crude peptide.
  • the peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo.
  • the crude peptide is solubilized in 20 mL of 20% acetonitrile/20%acetic acid/60%water and purified by RP- HPLC on a SymmetryPrep 7 ym C18 preparative column (19 x 300 mm, Waters) with linear gradients of 100% acetonitrile and 0.1% TF A/water buffer system (35-55% acetonitrile in 60 min).
  • the purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%.
  • the main pool purity of Example 14 is found to be 96.0%.
  • Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA salt.
  • SEQ ID NO: 17 The structure of SEQ ID NO: 17 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 17 is prepared substantially as described by the procedures of Example 15, except 4-(9-carboxy-nonyloxy)benzoic acid tert- butyl ester (WuXi AppTec, Shanghai, China) was used in the final coupling step.
  • the compound according to SEQ ID NO: 18 is prepared substantially as described by the procedures of Example 15, except 4-(4-Iodophenyl)butyric acid (WuXi AppTec, Shanghai, China) was used in the final coupling step.
  • SEQ ID NO: 19 The structure of SEQ ID NO: 19 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 19 is prepared substantially as described by the procedures of Example 15, except 4-(4-tert-Butylphenyl)butyric acid (WuXi AppTec, Shanghai, China) was used in the final coupling step.
  • SEQ ID NO: 19 The structure of SEQ ID NO: 19 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
  • the compound according to SEQ ID NO: 19 is prepared substantially as described by the procedures of Example 15, except Why acid (Sigma Aldrich) was used in the final coupling step.
  • Glucagon (referred to as Gcg) is a Reference Standard prepared at Eli Lilly and Company.
  • GLP-1, 7-36-NH 2 (referred to as GLP-1) is obtained from CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 mM aliquots in 100% DMSO).
  • GIP 1-42 (referred to as GIP) is prepared at Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above (>80% purity, 100 mM aliquots in 100% DMSO).
  • [ 125 I]-radiolabeled Gcg, GLP-1, or GIP is prepared using [ 125 I]-lactoperoxidase and obtained from Perkin Elmer (Boston, MA).
  • Stably transfected cell lines are prepared by subcloning receptor cDNA into a pcDNA3 expression plasmid and transfected into human embryonic kidney (HEK) 293 (hGcgR and hGLP-lR) or Chinese Hamster Ovary (CHO) (hGIPR) cells followed by selection with Geneticin (hGLP-lR and hGIPR) or hygromycin B (hGcgR).
  • HEK human embryonic kidney
  • hGcgR and hGLP-lR human embryonic kidney
  • hGIPR Chinese Hamster Ovary cells
  • Method 1 Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HC1, pH 7.5, and Roche CompleteTM Protease Inhibitors with EDTA.
  • the cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon ® pestle for 25 strokes.
  • the homogenate is centrifuged at 4°C at 1100 x g for 10 minutes.
  • the supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer and rehomogenized as described above.
  • the homogenate is centrifuged at 1100 x g for 10 minutes.
  • the second supernatant is combined with the first supernatant and centrifuged at 35000 x g for 1 hour at 4°C.
  • the resulting membrane pellet is resuspended in homogenization buffer containing protease inhibitors at approximately 1 to 3 mg/mL, quick frozen in liquid nitrogen and stored as aliquots in a - 80°C freezer until use.
  • Method 2 Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HC1, pH 7.5, 1 mM MgCl 2 , Roche CompleteTM EDTA-free Protease Inhibitors and 25 units/ml DNAse I (Invitrogen).
  • the cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon ® pestle for 20 to 25 strokes.
  • the homogenate is centrifuged at 4°C at 1800 x g for 15 minutes. The supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer (without DNAse I) and rehomogenized as described above.
  • the homogenate is centrifuged at 1800 x g for 15 minutes.
  • the second supernatant is combined with the first supernatant and centrifuged an additional time at 1800 x g for 15 minutes.
  • the overall supernatant is then centrifuged at 25000 x g for 30 minutes at 4°C.
  • the resulting membrane pellet is resuspended in homogenization buffer (without DNAse I) containing protease inhibitors at approximately 1 to 3 mg/mL and stored as aliquots in a -80°C freezer until use.
  • the equilibrium binding dissociation constants (K d ) for the various receptor/radioligand interactions are determined from homologous competition binding analysis instead of saturation binding due to high propanol content in the [ 125 I] stock material.
  • the K d values determined for the receptor preparations were as follows: hGcgR (3.9 nM), hGLP-lR (1.2 nM) and hGIPR (0.14 nM). r 125 Il -Glucagon Binding
  • the human Gcg receptor binding assays are performed using a Scintillation Proximity Assay (SPA) format with wheat germ agglutinin (WGA) beads (Perkin Elmer).
  • the binding buffer contains 25 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES), pH 7.4, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 0.1% (w/v) bacitracin (Research Products), 0.003% (w/v) Poly oxy ethyl enesorbitan monolaurate (TWEEN ® -20), and Roche CompleteTM Protease Inhibitors without EDTA.
  • Peptides and Gcg are thawed and 3 -fold serially diluted in 100% DMSO (10 point concentration response curves).
  • 5 pL serially diluted compound or DMSO is transferred into Coming ® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, at 1 pM final).
  • 50 pL human GcgR membranes 1.5 pg/well
  • 50 pL of WGA SPA beads 80 to 150 pg/well
  • the binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCE, 1 mM MgCE, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN ® -20, and Roche CompleteTM Protease Inhibitors without EDTA.
  • Peptides and GLP-1 are thawed and 3 -fold serially diluted in 100% DMSO (10 point concentration response curves).
  • 5 ⁇ L serially diluted compound or DMSO is transferred into Corning ® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, at 0.25 pM final).
  • the human GIP receptor binding assay is performed using an SPA format with WGA beads.
  • the binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCE, 1 mM MgCE, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN ® -20, and Roche CompleteTM Protease Inhibitors without EDTA.
  • Peptides and GIP are thawed and 3 fold serially diluted in 100% DMSO (10 point concentration response curves).
  • 5 pL serially diluted compound or DMSO is transferred into Corning ® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled GIP control (non-specific binding or NSB, at 0.25 pM final).
  • Raw CPM data for concentration curves of peptides, Gcg, GLP-1, or GIP are 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.
  • Data are analyzed using four-parameter (curve maximum, curve minimum, IC 50 , Hill slope) nonlinear regression routines (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland).
  • Geometric Mean io(Arithmetic Mean of Log Ki Values)
  • the Ki Ratio (Ki for native control peptide/Ki for test compound) at each receptor and each species is calculated.
  • the Ki Ratio is a rapid indication of the apparent affinity of a peptide compared to the native control peptide.
  • a Ki Ratio ⁇ 1 indicates that the test peptide has a lower affinity (higher Ki value) for the receptor than the native peptide, whereas a Ki Ratio >1 indicates that the test peptide has a higher affinity (lower Ki value) for the receptor than the native peptide.
  • GLP-1R human GLP-1 receptor
  • GIPR gastric inhibitory peptide receptor
  • GcgR Glucagon receptor
  • Pharmacological activity of the hGLPlR/GIPR peptides are determined in HEK293 cells stably expressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP-2R).
  • Each receptor over expressing cell line (20 m ⁇ ) is treated with the test peptide in DMEM (Gibco Cat# 31053) supplemented with 0.1% Casein (Sigma Cat# C4765), 250 mM IBMX, IX GlutaMAXTM (Gibco Cat# 35050), and 20 mM HEPES (HyClone Cat# SH30237.01) in a 20 m ⁇ assay volume. After 60 minute incubation at room temperature, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ).
  • the Lysis buffer containing cAMP-d2 conjugate (20 m ⁇ ) and the antibody anti-cAMP-Eu3+-Cryptate (20 m ⁇ ) are then added to determine the cAMP level.
  • HTRF signal is detected with an Envision 2104 plate reader (PerkinElmer). Fluorescent emission at 620 nm and at 665 nm is measured and the ratio between 620 nm and at 665 nm is calculated and then are converted to nM cAMP per well using a cAMP standard curve.
  • Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-liner regression fit with a variable slope (Genedata Screener 13).
  • EC50 is the concentration of compound causing half-maximal simulation in a dose response curve.
  • a relative EC50 value is derived by non-linear regression analysis using the percent maximal response vs. the concentration of peptide added, fitted to a four- parameter logistic equation.
  • Example and comparator molecules are conducted to determine the intrinsic potency of Example and comparator molecules performed in the presence of casein (instead of serum albumin) as a nonspecific blocker, which does not interact with the fatty acid moieties of the analyzed molecules.
  • Intracellular cAMP levels are determined by extrapolation using a standard curve. Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-linear regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve. Each relative EC50 value for the Geometric mean calculation is determined from a curve fitting.
  • Concentration response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter nonliner regression fit with a variable slope (Genedata Screener 13).
  • EC50 is the concentration of compound causing half-maximal simulation in a dose response curve.
  • the EC50 summary statistics are computed as follows:
  • GM 10 A (arithmetic mean of logio transformed EC50 values).
  • the log transform accounts for the EC50 values falling on a multiplicative, rather than an arithmetic scale.
  • test peptides are run plus the native ligands GIP and GLP-1, buffer only as baseline (minimum) and the highest concentration of the respective GIP and GLP-1 standard is used as maximum for calculations.
  • the test peptide is tested in 8 runs of the assay.
  • hGIP amide and hGLP-1 amide EC50 in Table 3 are illustrative of geometric mean values from a series of 18 assay values, and values will vary each day compared to the zero buffer. Accordingly, each Example will use the geometric mean of those values to normalize the Example assay runs.
  • Example compounds stimulate cAMP from human GLP-1R and GIPR in the presence of 0.1% casein.

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Abstract

An embodiment of the invention relates to method for increasing HDL-C in a patient in need thereof. An embodiment of the invention relates to a method for decreasing high blood pressure. An embodiment relates to a treatment method for a patient with refractory type 2 diabetes to provide normal HbA1c glycemia.

Description

GIP/GLP1 Dual Agonist Therapeutic Methods
The present invention relates to the field of medicine. Provided are treatment methods for refractor}' type 2 diabetes (T2D) in patients failing to reach recommended glucose targets with metformin and SGLT-2 treatment. Provided are methods relating to increasing HDL-C levels in a patient in need thereof. Provided are methods for lowering blood pressure in a patient in need thereof.
Glycated hemoglobin (HbAlc) is considered a key marker of glycemic control in diabetology. The American Diabetes Association (ADA) guidelines indicate that a patient with HbAlc less than or equal to 5.7% is considered normal glycemia. Patient treatment goals for HbAlc may vary by patient; however, persistently poorly controlled HbAlc contributes disproportionately to the development of complications associated with diabetes. Patients with type 2 diabetes often fail to achieve normal glycemia despite treatment using the ADA treatment paradigm. Despite not within normal range, the ADA guidelines suggest a reasonable HbAlc treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin. However, many patients fail to reach their HbAlc goals despite clinical treatment and are considered to have refractory type 2 diabetes.
Refractory type 2 diabetes is generally explained by an insulin secretory defect, or beta cell damage, becoming more and more profound with time, against a background of (relatively stable) insulin resistance. Patients living with type 2 diabetes for at least 8 years are more is likely to suffer from refractory type 2 diabetes. Therefore, there is a desire for a treatment method providing normal, or near normal glycemia, in a patient with refractory type 2 diabetes. There is a desire for a treatment method providing normal, or near normal glycemia, in a patient with refractory type 2 diabetes, wherein the patient has been treated for type 2 diabetes at least 8 years.
Nearly half of American adults have high blood pressure or low HDL-C. High blood pressure is a risk factor for stroke, coronary heart disease (CHD), and other significant health threats. Many patients with type 2 diabetes and obesity experience high blood pressure; however, approved treatments for diabetes typically have little or no effect on controlling high blood pressure. There is a desire for treatment options to manage high blood pressure. There is a desire for a method to treat high blood pressure in a patients with diabetes. Low serum levels of high-density lipoprotein cholesterol (HDL-C) is another known risk factor for coronary heart disease (CHD). Patients with type 2 diabetes often experience low serum levels of HDL-C; however, approved diabetes treatments generally fail to raise HDL-C. Longitudinal population studies have confirmed that HDL-C is inversely and independently associated with the risk of developing CHD. There is a desire for a drug therapy to increase HDL-C levels. There is a desire for a treatment method to raise HDL-C in a patient with type 2 diabetes.
The present invention provides methods for treating, preventing, or delaying high blood pressure, comprising administering a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof. The present invention further provides methods for treating, preventing, or delaying high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
The present invention provides methods for treating, preventing, or delaying low HDL-C, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof. The preset invention further provides methods for treating, preventing, or delaying HDL-C in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
The present invention provides methods for treating, preventing, or delaying refractory type 2 diabetes in a patient having type 2 diabetes for at least 8 years, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof
The present invention provides methods for treating refractory type 2 diabetes in a patient having type 2 diabetes for at least 8 years, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbA1c of greater than 10%.
In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbA1c of greater than 11%.
In an embodiment the patient in need of treatment for refractory' type 2 diabetes has an HbAlc treatment goal of 5.7%. In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbAlc treatment goal of less than or equal to 5.7%. In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbA1c treatment goal of 6%.
In an embodiment the patient in need of treatment for refractory type 2 diabetes has an HbA1c treatment goal of 7%.
The present invention provides methods for treating refractory type 2 diabetes in a patient who is non-responsive to metformin, SGLT-2 or metformin plus an SGLT-2 inhibitor, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof.
Accordingly, an embodiment provides a method for treating, preventing, or delaying high blood pressure in a patient in need thereof, compri sing administering an effective amount of a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof, to the patient once weekly. A further embodiment, provides a method for treating high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering an effective amount of a GIP/GLPl agonist or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of preventing or delaying high blood pressure in a patient, comprising administering a GIP/GLPl agonist in a therapeutically effective amount to the patient once weekly.
In another aspect, the present invention provides a method of preventing or delaying high blood pressure in a patient diagnosed with type 2 diabetes, comprising administering a GIP/GLPl agonist in a therapeutically effective amount to the patient once weekly.
In another aspect, the present invention provides use of a GIP/GLPl agonist for the preparation of a medicament for treating, preventing or delaying development of high blood pressure in a patient, wherein the medicament is administered once weekly.
The present invention provides methods for treating, preventing or delaying high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptabl e salt thereof to a patient in need of such treatment.
In an embodiment, the patient in need of treatment for high blood pressure has type 2 diabetes and is non-obese.
In an embodiment, the patient in need of treatment for high blood pressure has type 2 diabetes and obesity. In an embodiment, the patient in need of treatment for high blood pressure has refractory type 2 diabetes.
In an embodiment, the patient in need of treatment for high blood pressure has type 2 diabetes for at least 8 years.
Accordingly, an embodiment provides a method of treating, preventing or delaying development of hypertensive crisis in a patient with refractory type 2 diabetes, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In an embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes and is non-obese.
In an embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes and obesity.
In an embodiment, the patient in need of treatment for hypertensive crisis has refractory type 2 diabetes.
In an embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes for at least 8 years.
Accordingly, an embodiment provides a method of treating, preventing or delaying development of low HDL-C in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of preventing or delaying hypertensive crisis in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of preventing or delaying low HDL-C in a patient, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of treating high blood pressure in a patient receiving clinical treatment for type 2 diabetes using oral anti diabetic agents for at least 1 year, 2 years, 3, year, 4 year or 5 years wherein the patient’s HbA1c is > 7%, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
In another aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly for at least 30 weeks, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
In another aspect, the present invention provides a method of improving weight management in a patient with obesity and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing hypertensive crisis.
In another aspect, the present invention provides a method for treating high blood pressure in patient, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the patient’s weight is within a normal weight range for the patient.
In another aspect, the present invention provides a method of improving weight management in a patient with obesity and at risk for high blood pressure, comprising administering an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method provides a reduction in the risk of the patient experiencing high blood pressure.
In another aspect, there is provided a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in treating, preventing or delaying development of hypertensive crisis wherein the GIP/GLPl agonist is administered once weekly.
In another aspect, a method provides a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in treating, preventing or delaying development of high blood pressure wherein the GIP/GLP1 agonist or pharmaceutically acceptable salt thereof is administered once weekly.
In another aspect, an embodiment is the use of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating, preventing or delaying development of high blood pressure, wherein the medicament is administered once weekly.
In another aspect, provides the use of a GIP/GLP1 agonist for the preparation of a medicament for treating, preventing or delaying development of high blood pressure, wherein the medicament is administered once weekly.
In another aspect, an embodiment is the use of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating, preventing or delaying development of hypertensive crisis, wherein the medicament is administered once weekly.
In another aspect, provides the use of a GIP/GLP1 agonist for the preparation of a medicament for treating, preventing or delaying development of hypertensive crisis, wherein the medicament is administered once weekly.
In an embodiment, the GIP/GLP1 agonist is described and claimed in W02020/023386 (Eli Lilly).
As used herein, “hypertensive crisis” means blood pressure is dangerously high and may threaten patient organs or life. Hypertensive crisis is typically blood pressure that is at least 180/120. High blood pressure is generally 130/80 systolic/diastolic pressure.
As used herein, “refractory type 2 diabetes” refers to a patient unable to achieve their HbA1c goal using oral standard of care medications, such as metformin.
As used herein, “HbA1c goal” means the desired average HbA1c level to be achieved by the patient, as determined by the patient’s clinical treatment plan, and as measured using clinically accepted methods. Current ADA guidelines suggest a reasonable HbA1c treatment goal of less than or equal to 7% following current treatment options of diet, exercise, metformin, oral diabetes treatments, followed by basal insulin. However, many patients fail to reach their HbA1c goals despite clinical treatment and are considered to have refractory type 2 diabetes. In an embodiment, the HbA1c goal is 7% or less. In an embodiment, the HbA1c goal is 5.7% or less. Among men and women aged 49 to 82 yr, who were free of CHD at baseline in the Framingham study (during a follow up period of 12 yr), the participants with high HDL-C levels (in the 80th percentile) were at 50 per cent lower risk of cardiovascular events compared with participants with low HDL-C levels (in the 20th percentile)2. In the Prospective Cardiovascular Miinster (PROCAM) study (-4,500 volunteers, aged 16-65 yr, followed up for 6 yr), individuals with HDL-C <35 mg/dl were found to have four times higher coronary risk than those with HDL-C >35 mg/dl. See, Assmann G et al., High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996;124(Suppl):Sll-S20. Gordon et ak, suggested that every 1 mg/dl increase in HDL-C results in a decrease of 2 to 3 per cent of composite cardiovascular risk to an individual. Gordon DJ et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989;79:8-15. Results from Veterans Administration HDL Intervention Trial (VA-HIT) showed that in patients with initially low HDL-C, a modest increase of only 6 per cent of HDL-C significantly reduced both coronary morbidity and mortality up to 24 per cent. Rubins HB, et al., Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-8.
Current treatments to increase HDL-C may include lifestyle modification such as increased exercise and decrease dietary fat. Often lifestyle modification is insufficient to attain desired increase HDL-C. There is a need for treatment options for a patient in need of HDL-C elevation. There is a need for therapies to treat, prevent, or delay low HDL-C.
When used herein, the terms “treatment;’ “treat,” “treating,” and the like, are meant to include slowing or attenuating the progression of a disease, condition or disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if progression of the disorder or condition is not itself slowed or reversed. When used herein, the terms “prevent,” “preventing,” “prevention,” and the like, are meant to include avoidance of the onset of a disease, condition, disorder or symptom. When used herein, the terms “delay,” “delaying,” and the like, are meant to include increasing the duration of time that occurs until onset of a disease, condition, disorder or symptom. When used herein in connection with multiple outcomes, the term “composite” refers to the first to occur of any of the outcomes. The term “increase HDL-C” means the measured HDL-C level increases from baseline. In an embodiment, increase HDL-C change is statistically significant increase. In an embodiment, increase HDL-C is greater than 2% increase from baseline. In an embodiment, increase HDL-C is greater than 5% increase from baseline. In an embodiment, increase HDL-C is greater than 7% increase from baseline. In an embodiment, increase HDL-C is greater than 10% increase from baseline.
“Therapeutically effective amount” means the amount of GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for the methods and uses of the present invention, or pharmaceutical composition comprising a GIP/GLP agonist, or a pharmaceutically acceptable salt thereof, for the methods and uses of the present invention, that will elicit the biological or medical response of or desired therapeutic effect on the patient that is being sought by the researcher, medical doctor, or other clinician. An effective amount of GIP/GLP 1 agonist, or a pharmaceutically acceptable salt thereof, may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of GIP/GLP 1 agonist to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effect is outweighed by the therapeutically beneficial effects. In certain embodiments, the therapeutically effective amount of a GIP/GLP 1 agonist for use in the methods described herein is administered as an oral dosage form. In certain embodiments, the therapeutically effective amount of a GIP/GLP 1 agonist is administered once per day. In certain embodiments, the therapeutically effective amount of a GIP/GLP] agonist is administered twice per day. In certain embodiments, the therapeutically effective amount of a GIP/GLP 1 agonist is administered daily as an oral formulation.
Additional embodiments are described below:
In an embodiment, a method of improving glycemic control and increasing HDL- C, in a patient with type 2 diabetes mellitus, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly for at least 30 weeks. In an embodiment, a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 40 weeks. In an embodiment, a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 52 weeks.
High Blood Pressure and Normal HbA1c glycemia
A method of treating, preventing or delaying development of high blood pressure in a patient, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
In an embodiment, the high blood pressure is selected from the group consisting of high blood pressure and hypertensive crisis.
A method of preventing or delaying high blood pressure in a patient, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
A method of preventing or delaying high blood pressure in a patient, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient in an oral dosage form.
A method of improving glycemic control and treating, preventing or delaying high blood pressure in a patient in a patient diagnosed with type 2 diabetes mellitus, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
A method of improving glycemic control and treating, preventing or delaying high blood pressure in a patient in a patient diagnosed with type 2 diabetes mellitus, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient in an oral dosage form.
In an embodiment, the method results in a reduction in the risk of the patient experiencing high blood pressure. In an embodiment, the method results in a reduction in the risk of the patient experiencing hypertensive crisis. In an embodiment, the method results in a reduction in the risk of the patient experiencing clinically low HDL-C.
A method of improving glycemic control in a patient with type 2 diabetes mellitus, comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly, wherein the method results in a reduction in the risk of the patient experiencing high blood pressure. The method of any of the above embodiments wherein the patient has type 2 diabetes mellitus. A method of any of the above embodiments wherein the patient has refractory type 2 diabetes. A method of any of the above embodiments wherein the patient has type 2 diabetes for at least 8 years. A method of any of the above embodiments wherein the patient has type 2 diabetes for at least 10 years. A method of any of the above embodiments wherein the once weekly administration of a GIP/GLP1 agonist continue for at least 40 weeks. A method of any of the above embodiments wherein the patient is non-obese.
The method of any of the above embodiments wherein the patient has one or more of: T2DM; high blood pressure; reduced HDL-C; and obesity.
In an embodiment, the patient has either: multiple cardiovascular risk factors without high blood pressure or clinically significant high blood pressure.
In an embodiment, the patient has either: multiple cardiovascular risk factors or HbA1c level above 11%.
As used herein, “cardiovascular risk factors” means risk for cardiovascular disease selected from the group consisting of: current tobacco use (any form of tobacco); use of at least 1 approved lipid modifying therapy to treat hypercholesterolemia or a documented untreated low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L (100 mg/dL) within the past 6 months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/L (40 mg/dL) for men and <1.3 mmol/L (50 mg/dL) for women or triglycerides >2.3 mmol/L (150 mg/dL) within the past 6 months; use of at least 1 blood pressure medication to treat high blood pressure or untreated systolic blood pressure (SBP) >130mm Hg or diastolic blood pressure (DBP) >80 mmHg; measured waist circumference for a male 102 cm; for a female 88 cm.
As used herein, “non-obese” means a patient who is not obese by applicable standards. In an embodiment, the non-obese patient has body mass index is less than 30 BMI.
As used herein “comorbid” means that a patient is diagnosed with having 2 or more medical conditions.
In an embodiment, the patient’s risk of hypertensive crisis is reduced by at least about 14%. In an embodiment, the patient’s risk of hypertensive crisis is reduced by at least about 10%.
In an embodiment, the HDL-C levels are increased. In an embodiment, HDL-C levels are increased to a clinically desired level. In an embodiment, is a method of improving glycemic control and increasing HDL-C, in a patient with type 2 diabetes mellitus, comprising administering a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly for at least 30 weeks.
In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: hospitalization for high blood pressure or death.
In an embodiment, the risk of death or hospitalization for high blood pressure is reduced in a patient treated with an effective amount of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof.
In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: high blood pressure and HbA1c above 5.7%. In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL- C, high blood pressure, and HbA1c above 7%.
In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure and HbA1c above 5.7%.
In an embodiment, the risk of the occurrence of a composite of the following outcomes is reduced: low HDL-C, high blood pressure, and HbA1c above 6%.
A method of reaching normal HbA1c glycemia in a patient with refractory type 2 diabetes comprising administering a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to the patient once weekly.
In an embodiment, a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered using a dose escalation protocol.
In an embodiment, the patient fails to achieve HbA1c < 7% using one or two oral diabetes agents for at least one year prior to treatment using a GIP/GLPl agonist, or pharmaceutically acceptable salt thereof.
In an embodiment, the patient fails to achieve HbA1c < 8% using one or two oral agents for at least one year prior to treatment using a GIP/GLPl agonist, or pharmaceutically acceptable salt thereof. In an embodiment, the patient fails to achieve HbA1c <10% using one or two oral agents for at least one year prior to treatment using a GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof.
In an embodiment, once weekly GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 30 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 40 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 50 weeks. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 2 years. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 3 years. In an embodiment, once weekly GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration continues for at least 5 years.
In an embodiment, the patient was diagnosed with type 2 diabetes at least 8 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
In an embodiment, the patient was diagnosed with type 2 diabetes at least 10 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
In an embodiment, the patient was diagnosed with type 2 diabetes at least 13 years prior to GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, administration.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is at least 46 years old.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is at least 55 years old.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is at least 60 years old.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin and an SGLT2 oral agent.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered an SGLT2 oral agent. In an embodiment, the patient administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, is also administered metformin.
In an embodiment, the patient administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, is also administered a basal insulin.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin and a basal insulin.
In an embodiment the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered an SGLT2 and a basal insulin.
In an embodiment the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin, an SGLT2, and a basal insulin.
In an embodiment, the basal insulin is insulin glargine.
In an embodiment, the basal insulin is insulin Degludec.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered an SGLT2 oral pharmaceutical.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin, and 8GLT2 oral, and insulin Degludec.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin, and SGLT2 oral, and insulin Degludec.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin, an SGLT2 oral, and inulin glargine.
In an embodiment, the patient administered the GIP/GLPl agonist, or pharmaceutically acceptable salt thereof, is also administered metformin and insulin glargine.
In another aspect, the present invention provides a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in any of the above embodiments. In another aspect, the present invention provides use of a GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for any of the above embodiments.
In an embodiment, the GIP/GLP l agonist is a compound of Formula I: R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (SEQ ID NO:3) wherein:
Ri is absent or an Ac modification of the N-terminal amino group;
Xi is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY;
X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala; or Xi and X2 combine to form desH- ///[NHCO]-Aib;
X3 is selected from the group consisting of E, N, Aad, and cTA;
X6 is selected from the group consisting of F, aMeF, and aMeF(2F);
X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X11 is selected from the group consisting of S, aMeS, and D-Ser;
X12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi3 is selected from the group consisting of Me, Aib, L, aMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi4 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
Xi6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-
(CH2)qC02H;
Xi7 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2- [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X22 is selected from the group consisting of F and aMeF;
X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X25 is selected from the group consisting of Y and aMeY;
X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)q-C02H;
X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6),K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34-R2 (SEQ ID NO: 7), K[(2-
[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO: 9); wherein:
X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R2 is absent or a NH2 modification of the C-terminal group; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R2, then X31 is absent; wherein no more than one of X10, Xi2, X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid; and wherein no more than one of X30, X34, X39, and X40 may be C; and wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, Xi6, Xl7, Xl9, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula II, or pharmaceutically acceptable salt thereof, wherein:
Xi7 is an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; and X30 is selected from the group consisting of G-R2 and G; wherein if X30 is G, then X31 is selected from the group consisting of PX32X33X34- R2 (SEQ ID NO: 4), wherein X32 is S, X33 is S and X34 is G (SEQ ID NO: 15), and PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO: 16) (hereafter a “Formula III” compound).
In an embodiment is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein the Xj? amino acid is conjugated to the fatty acid via a linker (hereafter a “Formula Ilia” compound).
In an embodiment, the GIP/GLP1 agonist is a compound of Formula III and Ilia, or a pharmaceutically acceptable salt thereof, wherein:
X10 is selected from the group consisting of A, L, H, 3 Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, and cTA;
X12 is selected from the group consisting of I, S, and D-Ile;
Xi3 is selected from the group consisting of Me, Aib, L, and aMeL;
Xi4 is selected from the group consisting of L and K;
Xi6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, and R;
X19 is selected from the group consisting of Q, and A;
X20 is selected from the group consisting of Aib, Q, H, R, K, and aMeK;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I;
X23 is selected from the group consisting of I, L, A, G, F, H, E, and V;
X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P;
X26 is selected from the group consisting of L, and aMeL; X27 is selected from the group consisting of L, and I;
X28 is selected from the group consisting of E, A, S, and D-Glu;
X29 is selected from the group consisting of Aib, G, and A;
X30 is selected from the group consisting of G and G-R2; wherein if X30 is G; then X31 is selected from the group consisting of PX32X33X34- R2 (SEQ ID NO: 4), wherein X32 is S, X33 is S and X34 is G (SEQ ID NO: 15) and PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO: 16) (hereafter a “Formula Illb” compound).
In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
Ri is absent;
Xi and X2 do not combine to form desH- ///[NHCOj-Aib;
Xi7 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
Xi is Y;
X2 is Aib;
X3 is E;
X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;
X11 is S;
X12 is I;
Xi4 is L;
Xi6 is selected from the group consisting of K, E, Om, Dab, and Dap;
Xi7 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;
Xi9 is Q;
X20 is Aib;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;
X22 is F;
X23 is I; X24 is selected from the group consisting of S, Aad, D-Glu, and E;
X26 is L; and
X28 is selected from the group consisting of E and A.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:
Xi is Y;
X2 is Aib;
X3 is E;
X6 is aMeF(2F);
Xjo is selected from the group consisting of Y, 4-Pal, and V;
Xu is S;
X12 is I;
Xi3 is selected from the group consisting of L, Aib, and aMeL;
Xi4 is L;
Xi6 is selected from the group consisting of E, K, and Om;
Xu is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker,
Xi9 is Q;
X20 is Aib
X21 is selected from the group consisting of E, A, and T;
X22 is F;
X23 is I;
X24 is D-Glu;
X25 is selected from the group consisting of Y and αMeY;
X26 is L;
X27 is I;
X2s is E;
X29 is G;
X30 is G; and
X31 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S (SEQ ID NO: 16). In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein X½ is Orn, XB is aMeL, and X25 is Y. In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein C½ is E, Xn is aMeL, and X25 is Y. In an embodiment, the GIP/GLP1 agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein X½ is E, XB is aMeL, X10 is Y, and X25 is aMeY. In an embodiment, the GIP/GLPl agonist is a compound of Formula III, Ilia and Illb, or a pharmaceutically acceptable salt thereof, wherein C½ is Orn, Xj 3 is aMeL, X10 is 4Pal, and X25 is Y.
In an embodiment, the GIP/GLPl agonist is a compound of Formula I selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.
In an embodiment, the GIP/GLPl agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y, F, and D-Tyr; Xr, is F; and X13 is selected from the group consisting of Aib, L, and aMeL.
In an embodiment, the GIP/GLPl agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Riis absent; Xi is selected from the group consisting of Y, F, and D-Tyr; Xe is F; X13 is selected from the group consisting of Aib, L, and aMeL; X2 is Aib; X3 is E; X10 is Y; Xu is S; X12 is I; X14 is L; C½ is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, and R; X17 is an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X19 is Q; X20 is selected from the group consisting of Aib, Q, H, and K; X21 is selected from the group consisting of H, D, T, A, and E; X22 is F; X23 is I; X24 is selected from the group consisting of D-Glu and E; X26 is L; X27 is I; X28 is selected from the group consisting of E, A, S, and D-Glu; X29 is selected from the group consisting of Aib, G, and A; X30 is selected from the group consisting of C, G, and G-R2; X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 5), and PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6); wherein: X32is S; X33 is S; X34is selected from the group consisting of G and C; X35 is A; X36 is P; X37 is P; X38 is P; X39 is selected from the group consisting of C and S; and X40 is C. In an embodiment, the GIP/GLP1 agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y, F, and D-Tyr; Xr, is F; and X13 is selected from the group consisting of Aib, L, and aMeL; X28 is A; X29 G; X30is G; X31 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5); X34 is G; and X39 is S.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y and D-Tyr; and X13 is aMeL.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula I selected from the group consisting of SEQ ID NO:21, SEQ ID NO: 22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NQ:25, and SEQ ID NO:26, or a pharmaceutically acceptable salt thereof
In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI X1X2EGTX6TSDX10X11X12X13LDX16X17AQX20X21X22IX24X25LIX28GX30 (SEQ ID NO:27) wherein
Xi is selected from the group consisting of Y and RiY;
Ri is an Ac modification of the N-terminal amino group;
X2 IS Aib;
X6 is selected from the group consisting of αMeF and aMeF(2F);
X10 is selected from the group consisting of 4Pal, Y, aMeF, aMeF(2F), aMeL, aMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Me, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ1;
X11 is selected from the group consisting of S, aMeS, Aib, G, Dap, Ac5c, and Tie; X12 is selected from the group consisting of I and KZ1;
Xi3 is selected from the group consisting of aMeL and aMeF;
Xi6 is Orn;
Xi7 is selected from the group consisting of Q, I, and KZ1;
X20 is selected from the group consisting of Aib, Orn, 4Pal, aMeF, Ac5c, and Ac6c;
X21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal;
X22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, aMeF(2F), ChA, Bzt, and aMeF;
X24 is selected from the group consisting of D-Glu, E, G, and KZ1;
X25 is selected from the group consisting of Y, aMeY, aMeF, and KZ1;
X28 is selected from the group consisting of E, Orn, and KZ1;
X30 is selected from the group consisting of G, Orn, KZ1, K(ZI)R6, OrnR2, and GR2;
R2 is selected from the group consisting of X31, X3iSSG(SEQ ID NO:28), X31SSG-R3 (SEQ ID NO:29), X31SSGX35PPPX39 (SEQ ID NO:30), X31SSGX35PPPX39R3 (SEQ ID NO:31), X31SSGX35PPPX39X40 (SEQ ID NO:32), X31SSGX35PPPX39X40R3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NEE; R6 is selected from the group consisting of PSSG(SEQ ID NO:34), PSSG-R3 (SEQ ID NO:35), PSSGX35PPPX39 (SEQ ID NO:36), PS SGX35PPPX39R3 (SEQ ID NO:37), PSSGX35PPPX39X40 (SEQ ID NO:38), P S S GX35PPPX39X40R3 (SEQ ID NO:39), and a modification of the c-terminal group wherein the modification is NH2;
X31 is selected from the group consisting of P and KZ1;
X35 is selected from the group consisting of A and Orn;
X39 is selected from the group consisting of S and Orn;
X40 is KZ1;
R3 is a modification of the C-terminal group, wherein the modification is NEE; wherein two, and only two, of X10, X12, X17, X21, X24, X25, X28, X30, X31, and X40 are KZ1 or K(ZI)R6;
Zi is selected from the group consisting of R5 and -R4R5;
R4 is a linker; and R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
Provided is a compound of Formula VII:
X1X2EGTX6TSDX10X11X12X13LDX16X17AQX20X21X22IX24X25LIX28GX30 (SEQ
ID NO:40) wherein
Xi is selected from the group consisting of Y and RiY;
Ri is an Ac modification of the N-terminal amino group;
X2 is Aib;
X6 is selected from the group consisting of aMeF and aMeF(2F);
X10 is selected from the group consisting of 4Pal, Y, aMeF, aMeF(2F), aMeL, aMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ1 ;
X11 is selected from the group consisting of Ac5c, S, aMeS, Aib, G, Dap, and Tie; X12 is selected from the group consisting of I and KZ1;
Xi3 is selected from the group consisting of aMeL and aMeF;
Xi6 is Orn; X17 is selected from the group consisting of Q, I, and KZ1; X20 is selected from the group consisting of Aib, Orn, 4Pal, aMeF, Ac5c, and Ac6c;
X21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal;
X22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, aMeF(2F), ChA, Bzt, and aMeF;
X24 is selected from the group consisting of D-Glu, E, G, and KZ1;
X25 is selected from the group consisting of Y, aMeY, aMeF, and KZ1;
X28 is selected from the group consisting of E, Orn, and KZ1;
X30 is selected from the group consisting of G, Orn, KZ1, and GR2;
R2 is selected from the group consisting of X3iSSG(SEQ ID NO:28), X31SSG-R3 (SEQ ID NO:29), X31SSGX35PPPX39 (SEQ ID NO:30), X31 S SGX35PPPX39R3 (SEQ ID NO:31), X31 S S GX35PPPX39X40 (SEQ ID NO:32), X31SSGX35PPPX39X40R3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NEE;
X31 is selected from the group consisting of P and KZ1;
X35 is selected from the group consisting of A and Orn;
X39 is selected from the group consisting of S and Orn;
X40 is KZ1;
R3 is a modification of the C-terminal group, wherein the modification is NFE; wherein two, and only two, of X10, X12, X17, X21, X24, X25, X28, X30, X31, and X40 are KZ1;
Zi is selected from the group consisting of R5 and -R4R5; and R4 is a linker;
R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
In an embodiment, the GIP/GLP1 agonist is a peptide of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Glu)-CO-(CH2) 12-CO2H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-C02H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-( l 0-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(εK)-(y-Glu)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(εK)-(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH2)i2-C02H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Gl u)-(7-(4- carboxyphenoxy)heptanoyl),
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Gl u)-(8-(4- carboxyphenoxy)octanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(l l-(4- carboxyphenoxy)undecanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(2-[2-(2 -Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-PEG3-(y-Glu)-C0-(CH2)i2-C02H,
-PEG4-(y-Glu)-C0-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(l l-(4- carboxyphenoxy)undecanoyl,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Ahx-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Aoc-(y-Glu)-CO-(CH2)i2-C02H,
-Ahx-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-Aoc-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Ahx-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Aoc-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-Ahx-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl), -Aoc-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-PEG4-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl),
-PEG3-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Aoc-CO-(CH2)i2-C02H,
-PEG6-(y-Glu)-C0-(CH2)i2-C02H,
-PEG5-(y-Glu)-C0-(CH2)i2-C02H,
-PEG6-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl),
-PEG5-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-Trx-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-Trx-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Trx-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Trx-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)2-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)2-(10-(4- carboxyphenoxy)decanoyl),
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H, and -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl).
In an embodiment, the GIP/GLP1 agonist is a peptide of Formula I, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Glu)-CO-(CH2) 12-CO2H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)10-C02H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-( l 0-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H,
-(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(εK)-(y-Glu)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(εK)-(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2)i2-C02H
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH2)i2-C02H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Gl u)-(7-(4- carboxyphenoxy)heptanoyl),
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(y-Gl u)-(8-(4- carboxyphenoxy)octanoyl), and -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl).
In an embodiment, the GIP/GLP1 agonist is a peptide of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Zi is selected from the group consisting of
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert - butylphenyl)butanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl),
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-CO-(CH2)io-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-CO-(CH2)i4-CH3,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)i2-C02H,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(y-Glu)-CO-(CH2)i2-C02H, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )-(εK)-(y-Glu)-CO-(CH2) 12-CO2H, -(εK)-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )-(y-Glu)-CO-(CH2) 12-CO2H, -(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H, -(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(εK)-(y-Glu)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i2-C02H,
-(εK)-(εK)-(y-Glu)-C0-(CH2)i2-C02H,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2)i2-C02H, -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH2)i2-C02H, -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(7-(4- carboxyphenoxy)heptanoyl), -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(8-(4- carboxyphenoxy)octanoyl), and -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl).
In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of
-C0-(CH2)i2-C02H, -CO-(CH2)IO-C02H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4- iodophenyl)butanoyl), -(4-(4-tert-butyl phenyl )butanoyl ), -CO-(CH2)i4-CH3, -CO-(CH2)i2- CH3, -CO-(CH2)IO-CH3, -(7-(4-carboxyphenoxy)heptanoyl), -(8-(4- carboxyphenoxy)octanoyl), (1 l-(4-carboxyphenoxy)undecanoyl), -(12-(4- carboxyphenoxy)dodecanoyl), and -C0-(CH2)I4-C02H.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of
-C0-(CH2)i2-C02H, -CO-(CH2)IO-C02H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4- iodophenyl)butanoyl), -(4-(4-tert-butyl phenyl )butanoyl ), -CO-(CH2)i4-CH3, -CO-(CH2)i2- CH3, -CO-(CH2)IO-CH3, -(7-(4-carboxyphenoxy)heptanoyl), and -(8-(4- carboxyphenoxy)octanoyl). In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-, -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-,
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)2)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Trx-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-Trx-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Aoc-,
-(2- [2-(2-Amino-ethoxy)-ethoxy] -acetyl)- Aoc-(y-Glu)-, -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Ahx-(y-Glu)-, -PEG3-(y-Glu)-,
-PEG4-(y-Glu)-,
-PEG5-(y-Glu)-,
-PEG6-(y-Glu)-,
-Ahx-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-,
-Aoc-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-,
-(εK)-(y-Glu)-,
-(εK)-(y-Glu)-(y-Glu)-,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-,
-(εK)-(εK)-(y-Glu)-,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-, -(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2- Ami no-ethoxy)- ethoxyj-acetyl)-,
-(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)>-(y-Glu)-(2-[2-(2- Ami no-ethoxy )- ethoxyj-acetyl)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-, and
(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxyJ- acetyl)-(y-Glu)-.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-.
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)3-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(y-Glu)-,
-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(y-Glu)-,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-,
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-,
-(εK)-(y-Glu)-,
-(εK)-(y-Glu)-(y-Glu)-,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-,
-(εK)-(εK)-(y-Glu)-,
-(y-Glu)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-, and -(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy] -acetyl)-.
In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X17 and X31 are each KZ1. In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Xn and X24 are each KZ1. In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X17 and X21 are each KZ1. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X17 and X28 are each KZ1. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X17 and X40 are each KZ1. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X21 and X40 are each KZ1. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X21 and X28 are each KZ1. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein X24 and X28 are each KZ1.
In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein Xi is Y; Xe is aMeF(2F); X10 is selected from the group consisting of 4Pal, Y, and KZ1; X17 is selected from the group consisting of S, aMeS, and Aib; X12 is I; X13 is aMeL; C½ is Om; X17 is selected from the group consisting of I and KZ1; X20 is Aib; X21 is selected from the group consisting of KZ1 and E; X22 is selected from the group consisting of F and aMeF; X24 is selected from the group consisting of D-Glu and KZ1; X25 is aMeY; X28 is selected from the group consisting of E and KZ1; X30 is selected from the group consisting of G and GIG; R2 is selected from the group consisting of X31SSGX35PPPX39 (SEQ ID NO:30), X31SSGX35PPPX39R3 (SEQ ID NO:31), and X31 S S GX35PPPX39X40 (SEQ ID NO:32), and a modification of the c-terminal group wherein the modification is NFL; X31 is selected from the group consisting of P and KZ1; X35 is selected from the group consisting of A and Om; X39 is selected from the group consisting of S and Orn; X40 is selected from the group consisting of KZ1; R3 is a modification of the C-terminal group, wherein the modification is NFL; wherein one, and only one, selected from the group consisting of X10, X17, X21, X24, X28, and X31 is KZ1; Zi is -R4R5; R4 is a linker; and R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) i2- C02H)SSGAPPPS-NH2 (SEQ ID NO:41),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(l 0-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2 (SEQ ID NO: 17), Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4- iodophenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 18), Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-/<2/7-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)- a.MeY-LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 19) and Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io- CH3)SSGAPPPS-NH2 (SEQ ID NO: 19)
In an embodiment, the GIP/GLP1 agonist is a compond wherein the IQ linker is one to two amino acids selected from the group consisting of eK and y-Glu. In an embodiment the IG linker comprises from one to three (2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl) moieties. In an embodiment, the GIP/GLP1 agonist is a compound wherein the FG fatty acid moieties are conjugated to a lysine via an IG linker between the lysine and the IG fatty acid.
In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the IG linker comprises from zero to four amino acids; and from zero to three (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. In an embodiment, the GIP/GLPl agonist is a compound wherein the IG linker comprises from one to three amino acids each independently selected from the group consisting of eK and g-Glu. In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, wherein the R4 linker comprises from one to two amino acids each independently selected from the group consisting of eK and g-Glu. In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two Zi fatty acid moieties wherein each R5 fatty acid of the Zi moiety is conjugated to different lysines of the peptide via an R4 linker wherein, the R4 linker comprises from zero to two g-Glu amino acid residues. In an embodiment, the GIP/GLP1 agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two Zi fatty acid moieties wherein each R5 fatty acid of the Zi is conjugated to different lysines of the peptide via an R4 linker wherein R4 comprises from one to three amino acids and from one to three (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. In an embodiment, the GIP/GLPl agonist is a compound of Formula VI, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated to a different lysine of the peptide via an R4 linker wherein, R4 comprises from one to three amino acids each independently selected from the group consisting of eK and x-Glu; and from one to three (2-[2-(2-Amino-ethoxy)-ethoxyj- acetyl) moieties attached to the amino acid. In an embodiment, the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated to different lysines of the peptide via an R4 linker wherein R4 comprises up to three amino acids each independently selected from the group consisting of g-Glu and eK attached to one or two (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.
In an embodiment, the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated via an R4 linker, wherein the R4 linker has the following formula:
-(aK)a1-(Y-Glu)a2-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a3-(aK)b1-(y-Glu)b2-; wherein al is selected from the group consisting of 0, 1, and 2; a2 is selected from the group consisting of 0, 1, and 2; a3 is selected from the group consisting of 0, 1, 2, and 3; bl is 0 or 1; and b2 is 0 or 1. In an embodiment, the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated via an R4 linker wherein Zi is of the formula:
-(εK)ai-(Y-Glu)a2-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a3-(εK)b1-(Y-Glu)b2-CO-
(CH2)q-CCkH wherein wherein al is selected from the group consisting of 0, 1, and 2; a2 is selected from the group consisting of 0, 1, and 2; a3 is selected from the group consisting of 0, 1, 2, and 3; bl is 0 or 1; b2 is 0 or 1; and q is selected from the group consisting of 10, 12, 14 and 16.
In an embodiment, is a GIP/GLP1 agonist wherein al is 1, a2 is 0, a3 is 2, bl is 0, b2 is 1, and q is 12; and the structure is:
-(εK)-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)- C0-(CH2)i2-C02H.
In an embodiment, the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated via an R4 linker, wherein the R4 linker and R5 fatty acid components have the following formula: group consisting of 7, 8, 10, 11, and 12.
In an embodiment, the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties wherein the R5 fatty acid of the Zi is each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -(7-(4- carboxyphenoxy jheptanoyl ) and -(8-(4-carboxyphenoxy)octanoyl). In an embodiment, the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -(10-(4- carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), and -(4-(4-tert- butylphenyl)butanoyl).
In an embodiment, the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -CO-(CH2)i4-CH3, -CO-(CH2)i2-CH3, and -CO-(CH2)IO-CH3.
In an embodiment, the GIP/GLP1 agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -C0-(CH2)i2-C02H and -CO-(CH2)10-CO2H. In an embodiment, the GIP/GLPl agonist is a Formula VI compound, or a pharmaceutically acceptable salt thereof, comprising two of the same Zi fatty acid moieties each conjugated via an R4 linker, wherein the R5 fatty acid is selected from the group consisting of -CO-(CH2)IO- CH3 and -CO-(CH2)i2-CH3.
In an embodiment, the GIP/GLPl agonist is a compound wherein a R5 fatty acid is selected from the group consisting of -C0-(CH2)i2-C02H, -CO-(CH2)IO-C02H, -(10-(4- carboxyphenoxy jdecanoyl ), -(4-(4-iodophenyl)butanoyl), -(4-(4 -tert- butylphenyljbutanoyl), -CO-(CH2)i4-CH3, -CO-(CH2)i2-CH3, -CO-(CH2)IO-CH3, -(7-(4- carboxyphenoxy jheptanoyl ), and -(8-(4-carboxyphenoxy)octanoyl).
Certain GIP/GLPl agonist compounds are generally effective over a wide dosage range. For example, dosages for once weekly parenteral dosing may fall within the range of 0.05 mg to about 30 mg per person per week.
GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which is produced as a 30-amino acid, C-terminal amidated peptide (GLP-I7-36) (SEQ ID NO:2).
GIP is a 42 amino acid peptide (SEQ ID NO: 1), which, like GLP-1, is also known as an incretin, and plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose.
In an embodiment, a GIP/GLPl agonist compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 5 times the GLP1 receptor potency as measured by the casein cAMP assay described herein below, wherein the potency is normalized against native GIP and GLP on the day the assay is run. In an embodiment, a GIP/GLPl agonist compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 10 times the GLP1 receptor potency as measured by the casein cAMP assay, wherein the potency is normalized against native GIP and GLP on the day the assay is run.
As used herein the term “amino acid” means both naturally occurring amino acids and unnatural amino acids. The amino acids are typically depicted using standard one letter codes (e.g., L = leucine), as well as alpha-methyl substituted residues of natural amino acids (e.g., a-methyl leucine, or aMeL and a-methyl lysine, or aMeK) and certain other unnatural amino acids, such as alpha amino isobutyric acid, or “Aib,” “4Pal,” “Ora,” and the like. The structures of these amino acids appear below:
As used herein “Ora” means ornithine. As used herein “4Pa!” means 3-(4-Pyridyl)-L- alanine. As used herein “aMeF(2F)” means alpha-methyl 2-F -phenylalanine. As used herein “aMeY,” “aMeK,” and “aMeL” mean alpha methyl tyrosine, alpha methyl lysine, and alpha methyl leucine, respectively. As used herein, each of “e” and “D-Glu” means D-glutamic acid. As used herein each of “D-His” and “h” means D-histidine. As used herein each of “D-Tyr” and “y” means D-tyrosine. As used herein each of “D-Ser” and “s” means D-serine. As used herein each of “D-Ala” and “a” means D-alanine. As used herein, “aMeF(2F)” means alpha-methyl-F(2F) and alpha-methyl-Phe(2F). As used herein, “aMeF”, means alpha-methyl -F and alpha-methyl -Phe. As used herein, “aMeY”, means alpha-methyl -Tyr. As used herein “aMeK”, means alpha-methyl-Lys. As used herein, “aMeL”, means alpha-methyl-Leu. As used herein, “aMeS”, means alpha- methyl-serine and alpha-methyl-Ser. As used herein “αMeP”, means alpha-methyl- proline and alpha-methyl-Pro. As used herein, “desH”, means desHis. As used herein, “desY”, means desTyr.
As used herein, “AEEA” means (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl); “AEEA2” means (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2; and “AEEA3” means (2-[2- (2-Amino-ethoxy)-ethoxy]-acetyl)3.
As used herein, “Ahx” is 6-Aminohexanoyl-; “Aoc” is 8-Aminooctanoyl-;
“PEG3” is [3-(2-[2-(2-Amino-ethoxy)-ethoxy]-ethoxy)-propanoyl]-; “PEG4” is (3-[2-(2- [2-(2-Amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-propanoyl)-; “PEG5” is [3-(2-[2-(2-[2-(2- Amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-propanoyl]-; and “PEG6” is (3-[2-(2- [2-(2-[2-(2-Amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-ethoxy]-propanoyl)-. “Tie” is tert-Leucine.
When used herein in reference to one or more of the GIF or GLP-1 receptors, the terms “activity,” “activatejsj” “activat[ing]” and the like refers to the capacity of a compound, or a pharmaceutically acceptable salt thereof, to bind to and induce a response at the receptor(s), as measured using assays known in the art, such as the in vitro assays described below.
The affinity of GIP/GLP1 agonist compounds, or pharmaceutically acceptable salts thereof, for each of the GIP and GLP-1 receptors may be measured using techniques known for measuring receptor binding levels in the art, including, for example those described in the examples below, and is commonly expressed as a Ki value. The activity of the GIP/GLP1 agonist compounds at each of the receptors may also be measured using techniques known in the art, including for example the in vitro activity assays described below, and is commonly expressed as an EC50 value, which is the concentration of compound causing half-maximal simulation in a dose response curve
In an embodiment, the GIP/GLP1 agonist is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a potent GIPR/GLP-IR dual agonist that is a partial agonist on the GLP-1R as demonstrated by a Cell Membrane Guanosine 5'- (gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay, and a partial agonist on the GLP-1R as demonstarted by a P-arrestin-2 recruitment assay. In an embodiment, the GIP/GLPl agonist is a compound, or pharmaceutically acceptable salt thereof, wherein the compound stimulates GLP-1R induced activation of Gas in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate- [35S] (GTPyS) Binding Assay. In an embodiment, the GIP/GLP1 agonist is a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate- [35S] (GTPyS) Binding Assay, and 35% or less in the GLP-CHO Cell b- Arrestin. Recruitment Assay.
In an embodiment, a GIP/GLP1 agonist means a compound showing 35% or less in the GLP-CHO Cell b-Arrestin.Recruitment Assay and administering an effective amount of a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate- [35S] (GTPyS) Binding Assay.
When used herein, the term “effective amount” refers to the amount or dose of a compound of the present invention, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. An effective amount can be determined by a person of skill in the art using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a subject, a number of factors are considered, including, but not limited to: the species of mammal: its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
As used herein “EDT A” means ethylenediaminetetraacetic acid. As used herein “DMSO” means dimethyl sulfoxide. As used herein “CPM” means counts per minute.
As used herein “IBMX” means 3-isobutyl-l-methylxanthine. As used herein “LC/MS” means liquid chromatography/mass spectrometry. As used herein “HTRF” means homogeneous time-resolved fluorescence. As used herein “BSA” mean bovine serum albumin.
The invention is further illustrated by the following examples, which are not to be construed as limiting. As used herein “estimands” refers to- efficacy and treatment- regimen - evaluated to determine the efficacy of a GIP/GLP1 agonist due to requirements by certain regulatory agencies. The efficacy estimand is used to evaluate results in people prior to their discontinuation of study drug or initiating rescue therapy for persistent severe hyperglycemia. The treatment-regimen estimand - required by certain regulatory agencies including the U.S. Food and Drug Administration - evaluates the treatment effect in people in the study irrespective of adherence to the GIP/GLP1 agonist or introduction of rescue therapy for persistent severe hyperglycemia.
In other embodiments, present invention provides the following:
Embodiment 1. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of refractory type 2 diabetes in a patient, wherein the GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly.
Embodiment 2. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of high blood pressure in a patient, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly.
Embodiment 3. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use in raising HDL-C in a patient, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered once weekly. Embodiment 4. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 3, wherein the patient has type 2 diabetes for at least 8 years.
Embodiment 5. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 4, wherein the patient HbA1c goal is less than 7%.
Embodiment 6. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 5, wherein the patient HbA1c goal is equal to or less than 5.7%.
Embodiment 7. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 6, wherein the patient HbA1c is greater than 10%.
Embodiment 8. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 7, wherein the patient HbA1c is greater than 11%. Embodiment 9. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 8, wherein the patient age is at least 46 years.
Embodiment 10. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 9, wherein the patient age is at least 60 years old.
Embodiment 11. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 10, wherein the patient is taking an SGLT2 inhibitor.
Embodiment 12. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 11, wherein the patient is taking metformin.
Embodiment 13. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 12, wherein the patient is not administered a basal insulin.
Embodiment 14. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 13, wherein the patient fails to reach their HbA1c goal while taking metformin and an SGLT2 inhibitor. Embodiment 15. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 14, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 40 weeks.
Embodiment 16. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 15, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 50 weeks.
Embodiment 17. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 16, wherein the GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, is administered for at least 2 years. Embodiment 18. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 17, wherein the patient is non-ob ese.
Embodiment 19. A GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 18, wherein the patient has comorbid high blood pressure.
Embodiment 20. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 19, wherein the patient has comorbid low HDL-C.
Embodiment 21. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 17 or 19 to 20, wherein the patient has comorbid obesity.
Embodiment 22. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 21, wherein the patient has at least two cardiovascular risk factors.
Embodiment 23. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 21, wherein the patient has no cardiovascular risk factors.
Embodiment 24. A GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 23, wherein the patient has type 2 diabetes for at least 10 years.
EXAMPLES
Example 1. Clinical Trial using a GIP/GLPl Agonist The enrollment criteria, set forth in Table 1 below, are designed to include participants who are similar to patients seen within a typical diabetes practice, and include some patient with type 2 diabetes that is refractory to oral treatment. Geriatric patients are included. Study continues for 52 weeks.
Table 1. Enrollment Criteria Example 1.
The study is designed to consist of a screening visit followed by a single-blind 3- week placebo run-in period. Afterwards, patients are randomized to GIP/GLP1 agonist (dosed using an escalation dose protocol) or insulin degludec (standard titration protocol) and followed at approximately monthly intervals. Patients receiving insulin degludec follow standard insulin degludec titration protocol during the study. Study protocol includes blood pressure measurement at each visit and serum lipid profile at study initiation and at 52 weeks using standard clinical methods.
The mean dose of insulin degludec at 52 weeks is about 48 units per day. A greater percent of patients randomized to GIP/GLP1 agonist achieve an HbA1c of less than 7 percent, the American Diabetes Association’s recommended target for people with diabetes, or less than 5.7 percent - the level seen in people without diabetes - than patients randomized to insulin degludec.
Example 2. Clinical Trial using a GIP/GLP1 agonist The enrollment criteria, set forth in Table 2 below, include patients considered refractory to type 2 diabetes oral treatment; however, oral diabetes treatment continues through the study. Study continues for 40 weeks.
Clinical Trial 2, Table 2 Table 2. Enrollment Criteria Example 2.
The study is designed to consist of a screening visit followed by a 3-week run-in period. Afterwards, patients begin a 40-week randomized, double-blind study with a GIP/GLP1 agonist or placebo, as add-on to their previous treatment with insulin glargine with or without metformin. Insulin glargine dose was titrated throughout the study using a validated treat-to-target algorithm’. Patients are followed at approximately weekly intervals, then approximately monthly. Study protocol includes blood pressure measurement at each visit and serum lipid profile at study initiation and at 40 weeks using standard clinical methods. The study shows doses of a GIP/GLPl agonist can be useful for HbA1c reduction and weight reduction from baseline compared to placebo as an add-on to titrated insulin glargine with or without metformin in adults with type 2 diabetes using the clinical trial dosing.
Example 3: Clinical Trial using a GIP/GLPl agonist This study is a 4-week multiple ascending dose study investigating the safety and tolerability of the GIP/GLPl agonist of Example 7 administered as 4 once-weekly subcutaneous injections in patients with Type 2 Diabetes compared with placebo. Prespecified safety parameters to be studied include blood pressure.
The study includes 4 cohorts for treatment with the GIP/GLPl agonist. Cohorts 1 and 2 receive 4 fixed doses of 0.3 mg or 1 mg, respectively. Cohorts 3 and 4 receive weekly doses in stepwise increments as shown in Table 3.
Table 3: Dosing Scheme (in mg).
Criteria are established to enroll patients whose glycemic control is not well controlled on diet and exercise or stable dose of metformin. Baseline demographics of patients enrolled are provided below in Table 4.
Table 4: Baseline demographics.
Blood pressure results are provided in Table 5 below.
Table 5. Blood pressure results.
As seen in Table 5, mean systolic and diastolic blood pressure decreased at the end of the study period for each of GIP/GLP1 cohorts as compared to placebo.
PEPTIDE SYNTHESIS Example 4
Y - Aib-EGT -aMeF(2F)-TSD Y SI-aMeL-LDEK((2- [2-(2- Amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)i8-C02H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH2 (SEQ ID NO: 10).
The structure of SEQ ID NO: 10 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, K17, Aib20, D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:
The peptide backbone of Example 4 is synthesized using Fluorenylmetliyloxycarbonyl (Fmoc)/tert-ButyI (t-Bu) chemistry on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, AZ).
The resin consists of 1% DVB cross-linked polystyrene (F moc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.3-0.4 meq/g.
Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 and Boc-Tyr(tBu)~OH) was used for the tyrosine at position 1. Fmoc groups are removed prior to each coupling step (2 x 7 minutes) using 20% piperidine in DMF. All standard amino acid couplings are performed for 1 hour to a primary amine and 3 hour to a secondary amine, using an equal molar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoretical peptide loading. Exceptions are couplings to C fir-methylated amino acids, which are coupled for 3 hours. After completion of the synthesis of the peptide backbone, the resin is thoroughly washed with DCM for 6 times to remove residual DMF. The Mtt protecting group on the lysine at position 17 is selectively removed from the peptide resin using two treatments of 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (2 x 40-minute treatment).
Subsequent attachment of the fatty acid-linker moiety is accomplished by coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid α-t-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), mono-OtBu-eicosanedioic acid (WuXi AppTec, Shanghai, China). 3-Foid excess of reagents (AA: PyAOP: DIPEA=1 : 1 : 1 mol/mol) are used for each coupling that is 1-hour long.
After the synthesis is complete, the peptide resin is washed with DCM, and then thoroughly air-dried. The dry resin is treated with 10 raL of cleavage cocktail (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filtered off, washed twice each with 2 rnL of neat T’FA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20°C) to precipitate the crude peptide. The peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo. The crude peptide is solubilized in 20% acetonitrile/20%Acetic acid/60%water and purified by RP- HPLC on a Luna 5 μm Phenyl-Hexyl preparative column (21 x 250 mm, Pbenomenex) with linear gradients of 100% acetonitrile and 0.1% TF A/water buffer system (30-50% acetonitrile in 60 min). The purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%. The main pool purity of compound 1 is found to be 98.0%. Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA sail.
The molecular weight is determined by LC- MS (obsd: M+3 =1657.2; Calc M+3 = 1657.0). Example 5
Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)16-C02H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-
NH2
(SEQ ID NO:ll)
The structure of SEQ ID NO: 11 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Ornl6, K17, Aib20 D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 11 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC~ MS (obsd: M+3 =1642.6: Calc Yl· 3 =1642.8).
Example 6
Example 6 is a compound represented by the following description:
Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)18-C02H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-
NH2
(SEQ ID NO:12)
The structure of SEQ ID NO: 12 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Ornl6, K17, Aib20, D-Glu24, and Ser39, where the stmctures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 12 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3 =1651.8; Calc M+3 =1652.2). Example 7
Y - Aib-EGT -aMeF (2F)-TSD-4Pal-SI-aMeL-LD-Or n-K((2- [2-(2- Amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)16-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGPSSGAPPPS-NH2 (SEQ ID NO: 13)
The structure of SEQ ID NO: 13 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24 aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 13 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3
= 1642.5; Calc M+3 =1642.1). Example 8
Y-Aib-EGT-aMeF(2F)-TSDVSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)16-C02H)AQ-Aib-EFI-(D-Glu)-aMeY-
LIEGGPSSGAPPPS-NH2 (SEQ ID NO: 14)
The structure of SEQ ID NO: 14 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Oml 6, K17, Aib20, D-Glu24,aMeY25, and Ser39, where the structures of these amino acid residues have been expanded: The compound according to SEQ ID NO: 14 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M K3 =1626.1; Calc M+3 =1626.1).
Example 8 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)i8-C02H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO:21)
The structure of SEQ ID N0:21 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded: The compound according to SEQ ID NO:21 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3 =1602.5: Calc M+3 =1602.8). Example 10
Y-Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y- Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO:22)
The structure of SEQ ID NO:22 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO:22 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3 =1626.8; Calc M+3 =1626.8).
Example 11
(D-Tyr)-Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y- Glu)-C0-(CH2)18-C02H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO:23)
The structure of SEQ ID NO:23 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO:23 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC~ MS (obsd: M+3 =1626.6: Calc M÷3 =1626.8).
Example 12
(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)18-C02H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS- NH2 (SEQ ID NO:24)
The structure of SEQ ID NO:24 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, Oml6, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded: The compound according to SEQ ID NO:24 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3 =1602.4: Calc M+3 =1602.8). Example 13
(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2- (Y-Glu)-C0-(CH2)18-C02H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2 (SEQ
ID NO:25)
The structure of SEQ ID NO:25 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, K17, Aib20, aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO:25 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3
= 1631.3; Calc M+3 =1631.5).
Example 14
(D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(YYGlu)-C0-(CH2)18-C02H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2
(SEQ ID NO:26)
The structure of SEQ ID NO:26 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, aMeL13, Oml6, K17, Aib20, aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO:26 is prepared substantially as described by the procedures of Example 4. The molecular weight is determined by LC- MS (obsd: M+3 =1626.5: Calc M÷3 =1626.8).
PEPTTDE SYNTHESIS Example 15
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2- C02H)SSGAPPPS-NH2 (SEQ ID NO:41). The structure of SEQ ID NO:41 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
The peptide backbone of Example 15 is synthesized using Fluorenylmethyloxycarbonyl (Fmoc)/tert-Butyl (t-Bu) chemistry on a Symphony multiplex peptide synthesizer (Gyros Protein Technologies. Tucson, A Z).
The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.35 mmol/g. Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine residues at positions 17 and 31, and Boc-Tyr(tBu)-OH was used for the tyrosine residue at position 1. Fmoc groups are removed prior to each coupling step (2 x 7 minutes) using 20% piperidine in DMF. All standard amino acid couplings are performed for 1 hour, using an equal molar ratio of Fmoc amino acid (0.3 mM in DMF), diisopropylcarbodiimide (0.9 mM in DCM) and Oxyma (0.9 mM in DMF), at a 9-fold molar excess over the theoretical peptide loading. Exceptions are couplings to Ca- methylated amino acids, which are coupled for 3 hours. After completion of the synthesis of the peptide backbone, the resin is thoroughly washed with DCM to remove residual DMF. The Mtt protecting groups on the lysine residues at positions 17 and 31 are selectively removed from the peptide resin using 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (3 x 1 hour treatments), and the resin is thoroughly washed with DCM and DMF. Sub sequent attachment of the linker moieties is accomplished by stepwise coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.) and Fmoc-glutamic acid a-t-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), following the procedures described above for standard coupling and deprotection reactions. After removal of the final Fmoc protecting groups, mono-OtBu- tetradecanedioic acid (WuXi AppTec, Shanghai, China) is coupled overnight using a 4- fold excess of the fatty acid, diisopropylcarbodiimide, and Oxyma (1: 1 :1 mol/mol/mol) in 1 : 1 DCM/DMF. After the synthesis is complete, the peptide-resin is washed with DCM and then thoroughly dried under vacuum. The dry resin is treated with 10 mL of cleavage cocktail (trifluoroacetic acid: water: triisopropyl silane, 95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filtered off, washed twice each with 2 mL of neat TFA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20°C) to precipitate the crude peptide. The peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo. The crude peptide is solubilized in 20 mL of 20% acetonitrile/20%acetic acid/60%water and purified by RP- HPLC on a SymmetryPrep 7 ym C18 preparative column (19 x 300 mm, Waters) with linear gradients of 100% acetonitrile and 0.1% TF A/water buffer system (35-55% acetonitrile in 60 min). The purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%. The main pool purity of Example 14 is found to be 96.0%. Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA salt. The molecular weight is determined by LC- MS (obsd: M+3 =1853.9; calc M+3 =1854.1).
Example 16
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2 (SEQ ID NO:17)
The structure of SEQ ID NO: 17 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 17 is prepared substantially as described by the procedures of Example 15, except 4-(9-carboxy-nonyloxy)benzoic acid tert- butyl ester (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (obsd: M+3 =1887.1; calc M+3 =1887.4).
Example 17
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4- iodophenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 18) The structure of SEQ ID NO: 18 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 18 is prepared substantially as described by the procedures of Example 15, except 4-(4-Iodophenyl)butyric acid (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (obsd: M+3 =1875.1; calc M+3 =1875.2).
Example 18
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)- ethoxy |-acetyl )2-(y-Glu)-(4-(4-tert-butylphenyl )butanoyl ))AQ-Aib-E FI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 19)
The structure of SEQ ID NO: 19 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 19 is prepared substantially as described by the procedures of Example 15, except 4-(4-tert-Butylphenyl)butyric acid (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (obsd: M+3 =1828.3; calc M+3 =1828.7).
Example 19
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2- Amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)SSGAPPPS-NH2
(SEQ ID NO: 19).
The structure of SEQ ID NO: 19 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4PallO, aMeL13, Oml6, K17, Aib20, D-Glu24, aMeY25, K31 and Ser39, where the structures of these amino acid residues have been expanded:
The compound according to SEQ ID NO: 19 is prepared substantially as described by the procedures of Example 15, except Laurie acid (Sigma Aldrich) was used in the final coupling step. The molecular weight is determined by LC-MS (obsd: M+3 =1815.1; calc M+3 =1815.4).
Binding Assays
Glucagon (referred to as Gcg) is a Reference Standard prepared at Eli Lilly and Company. GLP-1, 7-36-NH2 (referred to as GLP-1) is obtained from CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 mM aliquots in 100% DMSO). GIP 1-42 (referred to as GIP) is prepared at Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above (>80% purity, 100 mM aliquots in 100% DMSO). [125I]-radiolabeled Gcg, GLP-1, or GIP is prepared using [125I]-lactoperoxidase and obtained from Perkin Elmer (Boston, MA).
Stably transfected cell lines are prepared by subcloning receptor cDNA into a pcDNA3 expression plasmid and transfected into human embryonic kidney (HEK) 293 (hGcgR and hGLP-lR) or Chinese Hamster Ovary (CHO) (hGIPR) cells followed by selection with Geneticin (hGLP-lR and hGIPR) or hygromycin B (hGcgR).
Two methods are used for the preparation of crude cell membranes.
Method 1 : Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HC1, pH 7.5, and Roche Complete™ Protease Inhibitors with EDTA. The cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon® pestle for 25 strokes. The homogenate is centrifuged at 4°C at 1100 x g for 10 minutes. The supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer and rehomogenized as described above. The homogenate is centrifuged at 1100 x g for 10 minutes. The second supernatant is combined with the first supernatant and centrifuged at 35000 x g for 1 hour at 4°C. The resulting membrane pellet is resuspended in homogenization buffer containing protease inhibitors at approximately 1 to 3 mg/mL, quick frozen in liquid nitrogen and stored as aliquots in a - 80°C freezer until use.
Method 2: Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HC1, pH 7.5, 1 mM MgCl2, Roche Complete™ EDTA-free Protease Inhibitors and 25 units/ml DNAse I (Invitrogen). The cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon® pestle for 20 to 25 strokes. The homogenate is centrifuged at 4°C at 1800 x g for 15 minutes. The supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer (without DNAse I) and rehomogenized as described above. The homogenate is centrifuged at 1800 x g for 15 minutes. The second supernatant is combined with the first supernatant and centrifuged an additional time at 1800 x g for 15 minutes. The overall supernatant is then centrifuged at 25000 x g for 30 minutes at 4°C. The resulting membrane pellet is resuspended in homogenization buffer (without DNAse I) containing protease inhibitors at approximately 1 to 3 mg/mL and stored as aliquots in a -80°C freezer until use.
Binding Determination Methods
The equilibrium binding dissociation constants (Kd) for the various receptor/radioligand interactions are determined from homologous competition binding analysis instead of saturation binding due to high propanol content in the [125I] stock material. The Kd values determined for the receptor preparations were as follows: hGcgR (3.9 nM), hGLP-lR (1.2 nM) and hGIPR (0.14 nM). r125Il -Glucagon Binding
The human Gcg receptor binding assays are performed using a Scintillation Proximity Assay (SPA) format with wheat germ agglutinin (WGA) beads (Perkin Elmer). The binding buffer contains 25 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES), pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w/v) bacitracin (Research Products), 0.003% (w/v) Poly oxy ethyl enesorbitan monolaurate (TWEEN®-20), and Roche Complete™ Protease Inhibitors without EDTA. Peptides and Gcg are thawed and 3 -fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 pL serially diluted compound or DMSO is transferred into Coming® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, at 1 pM final). Then, 50 μL [125I]-Gcg (0.15 nM final), 50 pL human GcgR membranes (1.5 pg/well) and 50 pL of WGA SPA beads (80 to 150 pg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 12 hours of incubation/settling time at room temperature. Final assay concentration ranges for peptides tested in response curves is typically 1150 nM to 0.058 nM and for the control Gcg from 1000 nM to 0.05 nM. r125Il-GLP-l Binding The human GLP-1 receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCE, 1 mM MgCE, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, and Roche Complete™ Protease Inhibitors without EDTA. Peptides and GLP-1 are thawed and 3 -fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 μL serially diluted compound or DMSO is transferred into Corning® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, at 0.25 pM final). Then, 50 pL [125I]-GLP-1 (0.15 nM final), 50 pL human GLP-1R membranes (0.5 pg/well and 50 pL of WGA SPA beads (100 to 150 pg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 5 to 12 hours of incubation/ settling time at room temperature. Final assay concentration ranges for peptides tested in response curves are typically 1150 nM to 0.058 nM and for the control GLP-1, 250 nM to 0.013 nM.
[125Il-GIP Binding
The human GIP receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCE, 1 mM MgCE, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, and Roche Complete™ Protease Inhibitors without EDTA. Peptides and GIP are thawed and 3 fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 pL serially diluted compound or DMSO is transferred into Corning® 3632 clear bottom assay plates containing 45 pL assay binding buffer or unlabeled GIP control (non-specific binding or NSB, at 0.25 pM final). Then, 50 pL [125I]-GIP (0.075-0.15 nM final), 50 pL human GIPR membranes (3 pg/well) and 50 pL of WGA SPA beads (100 to 150 pg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 2.5 to 12 hours of incubation/settling time at room temperature. Final assay concentration ranges for peptides tested in response curves is typically 1150 to 0.058 nM or 115 nM to 0.0058 nM and for the control GIP, 250 nM to 0.013 nM.
Binding Assay Data Analysis
Raw CPM data for concentration curves of peptides, Gcg, GLP-1, or GIP are 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. Data are analyzed using four-parameter (curve maximum, curve minimum, IC50, Hill slope) nonlinear regression routines (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland). The affinity constant (Ki) is calculated from the absolute IC50 value based upon the equation Ki = IC50/(l + D/Kd) where D is the concentration of radioligand used in the experiment, IC50 is the concentration causing 50% inhibition of binding and Kdis the equilibrium binding dissociation constant of the radioligand (described above). Values for Ki are reported as the geometric mean, with error expressed as the standard error of the mean (SEM) and n is equal to the number of independent replicates (determined in assays performed on different days). Geometric Means are calculated as follows:
Geometric Mean = io(Arithmetic Mean of Log Ki Values))
The Ki Ratio (Ki for native control peptide/Ki for test compound) at each receptor and each species is calculated. The Ki Ratio is a rapid indication of the apparent affinity of a peptide compared to the native control peptide. A Ki Ratio < 1 indicates that the test peptide has a lower affinity (higher Ki value) for the receptor than the native peptide, whereas a Ki Ratio >1 indicates that the test peptide has a higher affinity (lower Ki value) for the receptor than the native peptide. n=l/x means that only one value out of the total number of replicates (x) is used to express the mean. SEM is only calculated when n=2 or greater non-qualified results exist. Means are expressed as GeαMetric means with the standard error of the mean (SEM) and the number of replicates (n) indicated in parenthesis.
Table 6. In vitro Binding Affinity (Ki) of indicated Examples and comparator molecules for human GLP-1 R, GcgR and GIPR.
Table 7. In vitro Binding Affinity (Ki) of indicated Examples and comparator molecules for human GLP-1R, GcgR and GIPR. Binding Affinity cAMP Pharmacological Functional Assay in presence of casein
An additional set of cAMP assays are conducted in HEK293 cells expressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), Glucagon receptor (GcgR). Pharmacological activity of the hGLPlR/GIPR peptides are determined in HEK293 cells stably expressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP-2R). Each receptor over expressing cell line (20 mΐ) is treated with the test peptide in DMEM (Gibco Cat# 31053) supplemented with 0.1% Casein (Sigma Cat# C4765), 250 mM IBMX, IX GlutaMAXTM (Gibco Cat# 35050), and 20 mM HEPES (HyClone Cat# SH30237.01) in a 20 mΐ assay volume. After 60 minute incubation at room temperature, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). The Lysis buffer containing cAMP-d2 conjugate (20 mΐ) and the antibody anti-cAMP-Eu3+-Cryptate (20 mΐ) are then added to determine the cAMP level. After lh-incubation at room temperature, HTRF signal is detected with an Envision 2104 plate reader (PerkinElmer). Fluorescent emission at 620 nm and at 665 nm is measured and the ratio between 620 nm and at 665 nm is calculated and then are converted to nM cAMP per well using a cAMP standard curve. Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-liner regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve. A relative EC50 value is derived by non-linear regression analysis using the percent maximal response vs. the concentration of peptide added, fitted to a four- parameter logistic equation.
Using Homogeneous Time Resolved Fluorescence methods, assays are conducted to determine the intrinsic potency of Example and comparator molecules performed in the presence of casein (instead of serum albumin) as a nonspecific blocker, which does not interact with the fatty acid moieties of the analyzed molecules.
Intracellular cAMP levels are determined by extrapolation using a standard curve. Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-linear regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve. Each relative EC50 value for the Geometric mean calculation is determined from a curve fitting.
Concentration response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter nonliner regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve. The EC50 summary statistics are computed as follows:
Geometric mean:
GM = 10A(arithmetic mean of logio transformed EC50 values).
The standard error of the mean is reported:
SEM = geometric mean x (standard deviation of logio transformed EC50 values / square root of the # of runs) x loge of 10.
The log transform accounts for the EC50 values falling on a multiplicative, rather than an arithmetic scale.
Each day, the assay is run, the test peptides are run plus the native ligands GIP and GLP-1, buffer only as baseline (minimum) and the highest concentration of the respective GIP and GLP-1 standard is used as maximum for calculations. For illustration, as shown by Example 4, the test peptide is tested in 8 runs of the assay. For avoidance of doubt, hGIP amide and hGLP-1 amide EC50 in Table 3 are illustrative of geometric mean values from a series of 18 assay values, and values will vary each day compared to the zero buffer. Accordingly, each Example will use the geometric mean of those values to normalize the Example assay runs.
Table 8. Functional activation of hGLP-lR, hGIPR, hGcgR in the presence of 0.1% Casein.
As demonstrated by data in Table 8, Example compounds stimulate cAMP from human GLP-1R and GIPR in the presence of 0.1% casein.
Amino Acid Sequences SEQ ID NO: 1 GIP (Human)
Y AEGTFISD YSIAMDKIHQQDF VNWLL AQKGKKNDWKHNIT Q
SEQ ID NO:2 GLP-1 (7-36) (Human)
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2
SEQ ID NO: 3
R1X1X2X3GTX6TSDX10X11X12X13X14D-
X16X17AX1X20X21X22X23X24X25X26X27X28X29X30X31
SEQ ID NO:4
PX32 X33 X34-R2
SEQ ID NO: 5
PX32X33X34X35X36X37X38X39-R2
SEQ ID NO: 6
PX32X33X34X35X36X37X38X39X40-R2
SEQ ID NO: 7
K[(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H]X32X33X34-R2
SEQ ID NO: 8
K[(2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(Y-Glu)-CO-(CH2)q-
C02H]X32X33X34X35X36X37X38X39-R2
SEQ ID NO: 9 K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-
CO2H]X32X33X34X35X36X37X38X39X40-R2
SEQ ID NO: 10 Example 3
Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-
(Y-Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2
SEQ ID NO: 11
Example 4
Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)i6-C02H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2
SEQ ID NO: 12 Example 5
Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2
SEQ ID NO: 13 Example 6
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)i6-C02H)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGPSSGAPPPS-
NH2
SEQ ID NO: 14 Example 7
Y-Aib-EGT-aMeF(2F)-TSDVSI-aMeL-LD-Om-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)i6-C02H)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGPSSGAPPPS-
NH2
SEQ ID NO: 15 PSSG-R2 SEQ ID NO: 16 PSSGAPPPS-R-2
SEQ ID NO: 17
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-( l 0-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2
SEQ ID NO: 18
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-
[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))SSGAPPPS-
NH2
SEQ ID NO: 19
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-(4-(4-/<2/7-butyl phenyl )butanoyl))AQ-Aib-EFI-(D-Glu)-a.MeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-/<2/7- buty lpheny l)butanoy 1 )) S S GAPPP S -NH2
SEQ ID NO:20
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-
Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)SSGAPPPS-NH2
SEQ ID NO:21
Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-
(CH2)i8-C02H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH2 SEQ ID NO:22
Y- Aib-EGTFTSDYS I-aMeL-LDKK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(“/-G1U)- C0-(CH2)i8-C02H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2
SEQ ID NO:23
(D-Tyr)- Aib-EGTFTSD YSI-aMeL-LDK K((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl )2-(g- Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2
SEQ ID NO:24
(D-Tyr)- Aib-EGTFTSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2- (Y-Glu)-C0-(CH2)i8-C02H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH2
SEQ ID NO:25
(D-Tyr)- Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y- Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2
SEQ ID NO:26
(D-Tyr)- Aib-EGTFTSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2- (Y-Glu)-C0-(CH2)i8-C02H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2
SEQ ID NO:27
XIX2EGTX6TSDXIOXIIXI2XI3LDXI6XI7AQX2OX2IX22IX24X25LIX28GX3O
SEQ ID NO:28 X31SSG
SEQ ID NO:29 X31SSG-R3
SEQ ID NO:30 X31SSGX35PPPX39 SEQ ID NO: 31 X31SSGX35PPPX39R3
SEQ ID NO: 32 X31SSGX35PPPX39X40
SEQ ID NO:33 X31SSGX35PPPX39X40R3
SEQ ID NO: 34 PSSG
SEQ ID NO: 35 PSSG-R3
SEQ ID NO:36 PSSGX35PPPX39
SEQ ID NO:37 PSSGX35PPPX39R3
SEQ ID NO: 38 PSSGX35PPPX39X40
SEQ ID NO:39 PSSGX35PPPX39X40R3
SEQ ID NO:40
X1X2EGTX6TSDX10X11X12X13LDX16X17AQX20X21X22IX24X25LIX28GX30
SEQ ID NO:41 Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(Y-Glu)-C0-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 12-CO2H )SSGAPPPS-NH2

Claims

WE CLAIM:
1. A method of treating refractory type 2 diabetes in a patient in need thereof, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
2. A method as claimed by claim 1, wherein the patient has type 2 diabetes for at least 8 years.
3. A method as claimed by any one of Claims 1 or 2, wherein the patient HbA1c goal is less than 7%.
4. A method as claimed by any one of Claims 1 to 3, wherein the patient HbA1c goal is equal to or less than 5.7%.
5. A method as claimed by any one of Claims 1 to 4, wherein the patient HbA1c is greater than 10%.
6. A method as claimed by any one of Claims 1 to 4, wherein the patient HbA1c is greater than 11%.
7. A method as claimed by any one of Claims 1 to 6, wherein the patient age is at least 46 years.
8. A method as claimed by any one of Claims 1 to 7, wherein the patient age is at least 60 years.
9. A method as claimed by any one of Claims 1 to 8, wherein the patient is taking an SGLT2 inhibitor.
10. A method as claimed by any one of Claims 1 to 9, wherein the patient is taking metformin.
11. A method as claimed by any one of Claims 1 to 10, wherein the patient is not administered a basal insulin.
12. A method as claimed by any one of Claims 1 to 11, wherein the patient fails to reach their HbA1c goal while taking metformin and an SGLT2 inhibitor.
13. A method as claimed by any one of Claims 1 to 12, wherein the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, treatment continues for at least 40 weeks.
14. A method as claimed by any one of Claims 1 to 13, wherein the patient is administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, for at least 50 weeks.
15. A method as claimed by any one of Claims 1 to 14, wherein the patient is administered the GIP/GLP1 agonist, or pharmaceutically acceptable salt thereof, for at least 2 years.
16. A method as claimed by any one of Claims 1 to 15, wherein the patient is non-obese.
17. A method as claimed by any one of Claims 1 to 16, wherein the patient has comorbid high blood pressure.
18. A method as claimed by any one of Claims 1 to 17, wherein the patient has comorbid low HDL-C.
19. A method as claimed by any one of Claims 1 to 15 or 16 to 18, wherein the patient has comorbid obesity.
20. A method as claimed by any one of Claims 1 to 19, wherein the patient has at least two cardiovascular risk factors.
21. A method as claimed by any one of Claims 1 to 19, wherein the patient has no cardiovascular risk factors.
22. A method as claimed by any one of Claims 1 to 21, wherein the patient has type 2 diabetes for at least 10 years.
23. A method of treating high blood pressure in a patient in need thereof, comprising administering an effective amount of GIP/GLPl agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
24. A method as claimed by claim 23, wherein the patient has type 2 diabetes for at least 8 years.
25. A method as claimed by any one of Claims 23 or 24, wherein the patient has refractory type 2 diabetes.
26. A method as claimed by any one of Claims 24 or 25, wherein the patient HbA1c goal is less than 7%. 27. A method as claimed by any one of Claims 23 to 26 wherein the patient HbA1c goal is equal to or less than 5.7%.
28. A method as claimed by any one of Claims 23 to 27 wherein the patient HbA1c is greater than 10%.
29. A method as claimed by any one of Claims 23 to 28 wherein the patient HbA1c is greater than 11%.
30. A method as claimed by any one of Claims 23 to 29 wherein the patient age is at least 46 years.
31. A method as claimed by any one of Claims 23 to 30 wherein the patient age is at least 60 years old.
32. A method as claimed by any one of Claims 23 to 31 wherein the patient is taking an SGLT2 inhibitor.
33. A method as claimed by any one of Claims 23 to 32 wherein the patient is taking metformin.
34. A method as claimed by any one of Claims 23 to 33 wherein the patient is not administered a basal insulin.
35. A method as claimed by any one of Claims 23 to 34 wherein the patient fails to reach their HbA1c goal while taking metformin and an SGLT2 inhibitor.
36. A method as claimed by any one of Claims 23 to 35 wherein the GIP/GLP1 agonist treatment continues for at least 40 weeks.
37. A method as claimed by any one of Claims 23 to 36 wherein the patient has comorbid obesity.
38. A method as claimed by any one of Claims 23 to 37 wherein the patient is non-obese.
39. A method as claimed by any one of Claims 23 to 38 wherein the patient has comorbid low HDL-C.
40. A method as claimed by any one of Claims 23 to 39 wherein the patient has at least two cardiovascular risk factors.
41. A method as claimed by any one of Claims 23 to 40 wherein the high blood pressure is hypertensive crisis.
42. A method as claimed by any one of Claims 23 to 41 wherein the method prevents hypertensive crisis.
43. A method as claimed by any one of Claims 23 to 42 wherein the method prevents stroke.
44. A method for raising HDL-C in a patient in need thereof, comprising administering an effective amount of a GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly.
45. A method as claimed by claim 44, wherein the patient has type 2 diabetes for at least 8 years.
46. A method as claimed by any one of Claims 44 or 45, wherein the patient has refractory type 2 diabetes.
47. A method as claimed by any one of Claims 44 to 56 wherein the patient age is at least 46 years.
48. A method as claimed by any one of Claims 44 to 47 wherein the patient age is at least 60 years old.
49. A method as claimed by any one of Claims 44 to 48 wherein the patient is taking an SGLT2 inhibitor.
50. A method as claimed by any one of Claims 44 to 49 wherein the patient is taking metformin.
51. A method as claimed by any one of Claims 44 to 50 wherein the patient is not administered a basal insulin.
52. A method as claimed by any one of Claims 44 to 51 wherein the GIP/GLP1 agonist treatment continues for at least 40 weeks.
53. A method as claimed by any one of Claims 44 to 52 wherein the patient is non-obese.
54. A method as claimed by any one of Claims 44 to 53 wherein the patient has at least two cardiovascular risk factors.
55. A method as claimed by any one of Claim 44 to 54 wherein the patient has comorbid high blood pressure.
56. A method as claimed by any one of Claims 44 to 53 wherein the GIP/GLP1 agonist administration continues at least 50 weeks.
57. A method as claimed by any of claims 44 to 56 wherein once weekly administration of a GIP/GLP1 agonist is continued for at least 2 years.
58. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLPl agonist compound is of the formula:
R1X1X2X3GTX6T8DX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (SEQ ID NO:3) wherein:
Ri is absent or an Ac modification of the N-terminal amino group;
Xi is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY;
X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala; or Xi and X2 combine to form desH- ψ [NHCOj-Aib;
X3 is selected from the group consisting of E, N, Aad, and cTA;
Xe is selected from the group consisting of F, aMeF, and aMeF(2F);
X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X11 is selected from the group consisting of S, aMeS, and D-Ser;
X12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi3 is selected from the group consisting of Me, Aib, L, αMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi4 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
Xi6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)qC02H;
Xi7 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2- [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X22 is selected from the group consisting of F and aMeF;
X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X25 is selected from the group consisting of Y and aMeY;
X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)q-C02H;
X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO: 4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6),K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34-R2 (SEQ ID NO: 7), K[(2-
[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:9); wherein: X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R2, then X31 is absent; wherein no more than one of X10, Xi2, X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid; and wherein no more than one of X30, X34, X39, and X40 may be C; and wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid.
59. A method as claimed by any one of Claims 23 to 43 wherein the GIP/GLP1 agonist compound is of the formula:
R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (SEQ ID NO:3) wherein:
Ri is absent or an Ac modification of the N-terminal amino group;
X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY;
X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala; or Xi and X2 combine to form desH- ψ [NHCOj-Aib;
X3 is selected from the group consisting of E, N, Aad, and cTA;
X6 is selected from the group consisting of F, aMeF, and aMeF(2F);
X10 is selected from the group consisting of A, L, H, 3 Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X11 is selected from the group consisting of S, aMeS, and D-Ser;
X12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi3 is selected from the group consisting of Me, Aib, L, αMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X14 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
X16 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-
(CH2)qC02H;
X17 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2- [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X22 is selected from the group consisting of F and aMeF;
X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X25 is selected from the group consisting of Y and aMeY;
X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)q-C02H;
X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO: 4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6),K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34-R2 (SEQ ID NO: 7), K[(2-
[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:9); wherein: X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R2, then X31 is absent; wherein no more than one of X10, Xi2, X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid; and wherein no more than one of X30, X34, X39, and X40 may be C; and wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, Xi6, Xl7, Xl9, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid.
60. A method as claimed by any one of Claims 44 to 57 wherein the GIP/GLP1 agonist compound is of the formula:
R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (SEQ ID NO:3) wherein:
Ri is absent or an Ac a modification of the N-terminal amino group;
Xi is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY;
X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala; or Xi and X2 combine to form desH- ///[NHCOj-Aib;
X3 is selected from the group consisting of E, N, Aad, and cTA;
Xe is selected from the group consisting of F, aMeF, and aMeF(2F);
X10 is selected from the group consisting of A, L, H, 3 Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X11 is selected from the group consisting of S, aMeS, and D-Ser;
X12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
Xi3 is selected from the group consisting of Me, Aib, L, αMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qC02H;
X14 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
Xi6 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-
(CH2)qC02H;
Xi7 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2- [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X22 is selected from the group consisting of F and aMeF;
X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X25 is selected from the group consisting of Y and aMeY;
X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qC02H;
X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)q-C02H;
X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO: 4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6),K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34-R2 (SEQ ID NO: 7), K[(2-
[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H] X32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:9); wherein: X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO- (CH2)q-C02H];
X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H];
X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-C02H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof; wherein if X30 is G-R2, then X31 is absent; wherein no more than one of X10, Xi2, X13, X14, Xi6, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid; and wherein no more than one of X30, X34, X39, and X40 may be C; and wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, Xi6, Xl7, Xl9, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid.
70. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLP1 agonist compound is of the formula:
XiX2EGTX6TSDX10XiiXi2Xi3LDX16X17AQX2oX2iX22lX24X25LIX28GX3o
(SEQ ID NO:27) wherein
Xiis selected from the group consisting of Y and RfY;
Ri is an Ac modification of the N-terminal amino group;
X2is Aib;
X6 is selected from the group consisting of aMeF and aMeF(2F);
X is selected from the group consisting of 4Pal, Y, aMeF, aMeF(2F), aMeL, aMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Me, V,
4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ^
Xu is selected from the group consisting of S, aMeS, Aib, G, Dap, Ac5c, and Tie;
X is selected from the group consisting of I and KZ1;
Xi3 is selected from the group consisting of aMeL and aMeF;
Xi6 is Orn;
Xi7 is selected from the group consisting of Q, I, and KZ1;
X is selected from the group consisting of Aib, Om, 4Pal, aMeF, Ac5c, and Ac6c;
X is selected from the group consisting of E, KZb G, Om, and 4Pal;
X22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, aMeF(2F), ChA, Bzt, and aMeF;
X is selected from the group consisting of D-Glu, E, G, and KZ1;
X25 is selected from the group consisting of Y, aMeY, aMeF, and KZ,;
X28 is selected from the group consisting of E, Om, and KZ1;
Xsois selected from the group consisting of G, Orn, KZ1, K(ZI)R6, OrnR2, and GR2; R2 is selected from the group consisting of X3i, X3ISSG(SEQ ID NO:28), X3ISSG- R3 (SEQ ID NO:29), X31SSGX35PPPX39 (SEQ ID NO:30),
X31SSGX35PPPX39R3 (SEQ ID NO:31), X .SSGX .PPPX M (SEQ ID NO:32), X3ISSGX35PPPX39X OR3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is ME;
Reis selected from the group consisting of PSSG(SEQ ID NO:34), PSSG-R3 (SEQ ID NO: 35), PSSGX35PPPX39 (SEQ ID NO: 36), PSSGX35PPPX39R3 (SEQ ID NO:37), PSSGX ,PPPX .,X4O (SEQ ID NO:38), PSSGX35PPPX39X4oR3 (SEQ ID NO: 39), and a modification of the c-terminal group wherein the modification is NEE;
X3i is selected from the group consisting of P, and KZ,;
X35 is selected from the group consisting of A and Orn;
Xv, is selected from the group consisting of S and Om;
X4o is KZ1;
R3 is a modification of the C-terminal group, wherein the modification is MR; wherein two, and only two, of C30, X32, ¾, X2i, X24, X25, X28, X3o, X3i, and X40 are KZ1 or K(ZI)R6;
Z1 is selected from the group consisting of R5 and -R,R5;
R, is a linker; and R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
71. A method as claimed by any one of Claims 23 to 43 wherein the GIP/GLP1 agonist compound is of the formula:
X1X2EGTX6TSDX10X„XI2XI3LDX16X17AQX20X2IX22IX24X25LIX28GX30
(SEQ ID NO:27) wherein
X1 is selected from the group consisting of Y and R1Y;
R1 is an Ac modification of the N-terminal amino group;
X2is Aib;
X6 is selected from the group consisting of aMeF and aMeF(2F); X10 is selected from the group consisting of 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ.;
X11 is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tie;
X12 is selected from the group consisting of I and KZ,;
X13 is selected from the group consisting of αMeL and αMeF;
X16 is Om;
X17 is selected from the group consisting of Q, I, and KZ,;
X20 is selected from the group consisting of Aib, Om, 4Pal, αMeF, Ac5c, and Ac6c;
X21 is selected from the group consisting of E, KZb G, Om, and 4Pal;
X22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF;
X24 is selected from the group consisting of D-Glu, E, G, and KZ,;
X25 is selected from the group consisting of Y, αMeY, ctMeF, and KZ,;
X28 is selected from the group consisting of E, Om, and KZ,;
X30is selected from the group consisting of G, Om, KZ,, K(Z.)R6, OmR2, and
GR2;
R2 is selected from the group consisting of X31, X3.SSG(SEQ ID NO:28), X31SSG- R3 (SEQ ID NO 29), X31SSGX35PPPX39 (SEQ ID NO: 30), X3.SSGX35PPPX39R3 (SEQ ID NO 31), X3.SSGX35PPPX39X4o (SEQ ID NO: 32), X3ISSGX35PPPX39XIOR3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NH2;
R6 is selected from the group consisting of PSSG(SEQ ID NO:34), PSSG-R3 (SEQ ID NO 35), PSSGX35PPPX39 (SEQ ID NO: 36), PSSGX35PPPX39R3 (SEQ ID NO 37), PSSGX35PPPX39X4O (SEQ ID NO: 38), PSSGX35PPPX39X4oR3 (SEQ ID NO:39), and a modification of the c-terminal group wherein the modification is NH2;
X3. is selected from the group consisting of P, and KZ,;
X35 is selected from the group consisting of A and Om;
X39 is selected from the group consisting of S and Om; X40 is KZ1;
R3 is a modification of the C -terminal group, wherein the modification is NH2; wherein two, and only two, of X,o, Xu, X,7, X2b X24, X -2255,, X28, X30, X3,, and X40 are KZ. or K(Z1)R6;
Zi is selected from the group consisting of R5 and -R4R5;
R4 is a linker; and
R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
72. A method as claimed by any one of Claims 44 to 57 wherein the GIP/GLP1 agonist compound is of the formula:
X1X2EGTX6TSDX10 X11X12X1 LDX16X17AQX20 X21X22IX24X2.LIX28GX 11
(SEQ ID NO 27) wherein
X, is selected from the group consisting of Y and RiY;
Ri is an Ac modification of the N-terminal amino group;
X2is Aib;
X6 is selected from the group consisting of αMeF and αMeF(2F);
X10 is selected from the group consisting of 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4c, Ac5c, Ac6c, Bip, INal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ,;
X11 is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tie;
X,2 is selected from the group consisting of I and KZ,;
X13 is selected from the group consisting of αMeL and αMeF;
X16 is Om;
X20 is selected from the group consisting of Q, I, and KZ,;
X20 is selected from the group consisting of Aib, Om, 4Pal, αMeF, Ac5c, and Ac6c;
X21 is selected from the group consisting of E, KZ,, G, Om, and 4Pal;
X22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, INal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF;
X24 is selected from the group consisting of D-Glu, E, G, and KZ,; X25 is selected from the group consisting of Y, αMeY, ctMeF, and KZ,;
X28 is selected from the group consisting of E, Om, and KZ,;
X30is selected from the group consisting of G, Om, KZ,, K(Z,)R«, OmR2, and
GR2;
R2 is selected from the group consisting of X3i, X3,SSG(SEQ ID NO:28), X3,SSG- R3 (SEQ ID NO:29), X31SSGX35PPPX39 (SEQ ID NO: 30), X31SSGX35PPPX39R3 (SEQ ID NO:31), X31SSGX35PPPX39X4o (SEQ ID NO: 32), X31SSGX35PPPX39XIOR3 (SEQ ID NO:33), and a modification of the c-terminal group wherein the modification is NH2;
Reis selected from the group consisting of PSSG(SEQ ID NO:34), PSSG-R3 (SEQ ID NO:35), PSSGX35PPPX39 (SEQ ID NO: 36), PSSGX35PPPX39R3 (SEQ ID NO:37), PSSGX35PPPX39X4O (SEQ ID NO: 38), PSSGX35PPPX39X4oR3 (SEQ ID NO:39), and a modification of the c-terminal group wherein the modification is NH2;
X3I is selected from the group consisting of P, and KZ,;
X35 is selected from the group consisting of A and Om;
X39 is selected from the group consisting of S and Om;
X40 is KZi;
R3 is a modification of the C-terminal group, wherein the modification is NH2; wherein two, and only two, of X10, X12, X1 7, , X21,, X24, X -2255,, X28, X30, X31, and X40 are KZ, or K(Z,)R6;
Zi is selected from the group consisting of R5 and -R4R5;
R4 is a linker; and
R5 is a fatty acid; or a pharmaceutically acceptable salt thereof.
73. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.
74. A method as claimed by any one of Claims 23 to 43 wherein the GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.
75. A method as claimed by any one of Claims 44 to 57 wherein the GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID
NO: 13, and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.
76. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLP1 agonist compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24,
SEQ ID NO.25, and SEQ ID NO.26.
77. A method as claimed by any one of Claims 23 to 43 wherein the GIP/GLP1 agonist compound, or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO:21, SEQ ID NO.22, SEQ ID N():23, SEQ ID NO:24,
SEQ ID NO:25, and SEQ ID NG:26.
78. A method as claimed by any one of Claims 44 to 57 wherein the GIP/GLP1 agonist compound, or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID N0.21, SEQ ID NG:22, SEQ ID NO:23, SEQ ID NO:24,
SEQ ID NO:25, and SEQ ID NO: 26.
79. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLP I agonist is a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2- C02H)SSGAPPPS-NH2 (SEQ ID NO:41),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetylf-(y-Glu)-( l 0-(4-carboxyphenoxy)decanoy1))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl)2-(y-Glu)-(l 0-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2 (SEQ ID NO: 17), Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl ),-(y-Gl u)-(4-(4- iodophenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 18), Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxyj-acetyl )2-(y-Glu)-(4-(4-/e/7-butyl phenyl )butanoyl))AQ-Ai b-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 19), and Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io- CH3)SSGAPPPS-NH2 (SEQ ID NO: 19).
80. A method as claimed by any one of Claims 23 to 43 wherein the GIP/GLP1 agonist is a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2- C02H)SSGAPPPS-NH2 (SEQ ID NO:41),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2 (SEQ ID NO: 17),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-
LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4- iodophenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 18),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 19), and
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2- Ami no-ethoxy )-ethoxy]-acetyl),-(y-Glu)-CO-(CH,) 10- CH3)SSGAPPPS-NH2 (SEQ ID NO: 19).
81. A method as claimed by any one of Claims 44 to 57 wherein the GIP/GLP1 agonist is a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)i2-C02H)AQ-Aib-EFI-(D-Glu)-aMeY- LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i2- C02H)SSGAPPPS-NH2 (SEQ ID NO:41),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(10-(4- carboxyphenoxy)decanoyl))SSGAPPPS-NH2 (SEQ ID NO: 17),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-
LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4- iodophenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 18),
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-(4-(4-ter/-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)- aMeY-LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-(4-(4-tert- butylphenyl)butanoyl))SSGAPPPS-NH2 (SEQ ID NO: 19), and
Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-CH3)AQ-Aib-EFI-(D-Glu)-aMeY-
LIEGGK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)io-
CH3)SSGAPPPS-NH2 (SEQ ID NO: 19).
82. A method as claimed by any one of Claims 1 to 22 wherein the GIP/GLP1 agonist is a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay, coadministered with a compound showing 35% or less in the GLP-CHO Cell b- Arrestin.Recruitment Assay.
83. A method as claimed by any one of Claims 1 to 22 wherein GIP/GLP1 agonist is a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay is co administered with a compound of a compound showing 35% or less in the GLP- CHO Cell b-Arrestin. Recruitment Assay.
84. A method as claimed by any one of Claims 23 to 43 wherein GIP/GLP1 agonist is a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay is co administered with a compound of a compound showing 35% or less in the GLP- CHO Cell b-Arrestin. Recruitment Assay.
85. A method as claimed by any one of Claims 44 to 57 wherein GIP/GLP1 agonist is a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay is co administered with a compound of a compound showing 35% or less in the GLP- CHO Cell b-Arrestin. Recruitment Assay.
EP22706153.8A 2021-02-17 2022-02-02 Gip/glp1 dual agonist therapeutic methods Pending EP4294423A1 (en)

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