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CN-121975020-A - Co-agonists of GLP-1 and the amylin receptor

CN121975020ACN 121975020 ACN121975020 ACN 121975020ACN-121975020-A

Abstract

The present invention relates to compounds comprising a GLP-1 receptor agonist and an amylin receptor agonist. The invention also relates to pharmaceutical formulations suitable for, but not limited to, oral administration comprising such compounds. The compounds and pharmaceutical formulations comprising the same are useful in the medical treatment of subjects suffering from overweight, obesity and related co-diseases.

Inventors

  • T. Crusoe
  • A. L.B. kodal
  • J. Madsen
  • S. Ostegard
  • W. F.J. hogendorf
  • C. W. tornoer
  • L. Schaeffer
  • A.R. Madsen

Assignees

  • 诺和诺德股份有限公司

Dates

Publication Date
20260505
Application Date
20211217
Priority Date
20201218

Claims (15)

  1. A glp-1 receptor-amylin receptor co-agonist comprising a polypeptide (R1) according to formula I: Z1-Z2-Z3, comprising 1-3 lysine (Lys, K) residues and no disulfide bonds, wherein: kou Z1 is a GLP-1 receptor agonist peptide comprising up to 9 amino acid modifications relative to SEQ ID NO 1, provided that Z1 does not comprise isoleucine (Ile, I) at position 22; kou Z2 is an optional peptide linker; kou Z3 is an amylin receptor agonist peptide comprising a C-terminal amide and up to 7 amino acid modifications relative to SEQ ID NO: 79, provided that Z3 does not comprise proline (Pro, P) at position 12; and further comprising 1-3 extensions (R2-R3) linked to said polypeptide (R1) through said 1-3 lysine (Lys, K) residues.
  2. 2. The GLP-1 receptor-amylin receptor co-agonist of claim 1 wherein the GLP-1 receptor agonist peptide (Z1) comprises 0-3 lysine (Lys, K) residues at any one of positions 9, 10, 12, 16, 19, 20, 21, 24, 25, 28, 29, 30 and/or 31, or a combination thereof, relative to SEQ ID NO 238 or 255.
  3. 3. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims, wherein the GLP-1 receptor agonist peptide (Z1) comprises 2 lysine (Lys, K) residues at positions relative to SEQ ID NO 238 or 255: kou 12 and any of 21, 30 or 31, or Kou 21, 21 and 30 or 31; preferably, at the following locations: kou 12 and 21 or 30, or Kou 21, 21 and 31.
  4. 4. The GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims wherein the GLP-1 receptor agonist peptide (Z1) comprises 1 lysine residue (Lys, K) at any one of positions 12, 20, 21, 28, 30 or 31, preferably 1 lysine (Lys, K) residue at position 31.
  5. 5. The GLP-1 receptor-amylin receptor co-agonist according to any of the preceding claims wherein the peptide linker (Z2) comprises 0-3 lysine (Lys, K) residues, such as 1-2 lysine (Lys, K) residues, preferably 1 lysine (Lys, K) residue.
  6. 6. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims, wherein the amylin receptor agonist peptide (Z3) comprises 0-3 lysine (Lys, K) residues at any one of positions 1,2, 3, 7, 14, 18, 20, 23 and/or 29, preferably 1 lysine (Lys, K) residue at any one of positions 14, 18, 20, 23, 29, even more preferably 1 lysine (Lys, K) residue at position 18, relative to SEQ ID NO 240 or SEQ ID NO 256.
  7. 7. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims comprising a GLP-1 receptor agonist peptide (Z1) according to formula II (SEQ ID NO: 255): Xaa1-Xaa2-Glu-Gly-Thr-Phe-Thr-Ser-Xaa9-Xaa10-Ser-Xaa12-Tyr-Leu-Glu-Xaa16-Xaa17-Ala-Xaa19-Xaa20-Xaa21-Phe-Ile-Xaa24-Xaa25-Leu-Val-Xaa28-Xaa29-Xaa30-Xaa31; Wherein the method comprises the steps of Xaa1 is His (H) or Imp, Xaa2 is Aib, ala (A), gly (G) or Trp (W), Xaa9 is Asp (D) or Lys (K), Xaa10 is Lys (K) or Val (V), Xaa12 is Lys (K), arg (R) or Ser (S), Xaa16 is Glu (E), gly (G) or Lys (K), Xaa17 is Gln (Q) or Lys (K), Xaa19 is Ala (A) or Val (V), Xaa20 is Lys (K) or Arg (R), Xaa21 is Glu (E) or Lys (K), Xaa24 is Ala (A), glu (E), Xaa25 is Lys (K) or Trp (W), Xaa28 is Lys (K) or Arg (R), Xaa29 is Lys (K) or Gly (G), Xaa30 is Ala (A), gly (G), lys (K), arg (R) or absent, Xaa31 is Ala (A), lys (K), gly (G), gln (Q) or absent.
  8. 8. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims comprising an amylin receptor agonist peptide (Z3) according to formula III (SEQ ID NO: 256): Xaa1-Xaa2-Xaa3-Leu-Ser-Thr-Xaa7-Ala-Leu-Gly-Arg-Leu-Ser-Xaa14-Glu-Leu-His-Xaa18-Leu-Xaa20-Thr-Leu-Xaa23-Arg-Thr-Glu-Thr-Gly-Xaa29-Gly-Ser-Pro, Wherein: xaa1 is Ala (A) or absent, Xaa2 is Lys (K) or Ser (S), Xaa3 is Glu (E) or Arg (R), Xaa7 is Ala (A) or Glu (E), Xaa14 is Ala (A) or Lys (K), Xaa18 is Glu (E), lys (K) or Gln (Q), Xaa20 is Ala (A) or Lys (K), Xaa23 is Lys (K) or Pro (P), Xaa29 is Ser (S) or Lys (K).
  9. 9. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims comprising: kou one to two C14-C20 diacids, more preferably one C16-C20 diacid or two C14-C18 diacids, even more preferably a single C18 diacid, or Kou 1-2 are selected from the elongations listed in table 2.
  10. 10. The GLP-1 receptor-amylin receptor co-agonist of any one of the preceding claims comprising a polypeptide represented by any one of SEQ ID NOs 117-236, preferably a polypeptide represented by SEQ ID NO 153.
  11. 11. The GLP-1 receptor-amylin receptor co-agonist according to any of the preceding claims, which is any of the compounds listed in example 1a, preferably any of the compounds listed in table 5.
  12. Glp-1 receptor-amylin receptor co-agonist which is H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K ([ 2- [2- [2- [ [ (4S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butyryl ] amino ] ethoxy ] acetyl ]) -GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide: Or alternatively H-Aib-EGTFTSDVS-K ([ 2- [2- [ [ (4S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butanoyl ] amino ] ethoxy ] acetyl ]) -YLEEQAAREFIAWLVRGRGGGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide: Or alternatively H-Aib-EGTFTSDVSSYLEEQAAREFIAWLVRGR-K ([ 2- [2- [2- [ [ (4S) -4-carboxy-4- (19-carboxynonacarbonamido) butanoyl ] amino ] ethoxy ] acetyl ]) -GGGGEASELSTAALGRLSAELHELATLPRTETGSGSP-amide: 。
  13. 13. A pharmaceutical formulation comprising a GLP-1 receptor-amylin receptor co-agonist according to any one of the preceding claims.
  14. 14. The GLP-1 receptor-amylin receptor co-agonist of any one of claims 1-12, or the pharmaceutical formulation of claim 13, for use as a medicament.
  15. 15. The GLP-1 receptor-amylin receptor co-agonist of any one of claims 1-12, or the formulation of claim 13, for use in treating a subject having an initial Body Mass Index (BMI) of 27 or higher, such as 30 or higher, optionally in the presence of at least one weight-related co-disease, diabetes, optionally in the presence of at least one weight-related co-disease, cardiovascular disease, non-steroidal steatohepatitis and/or cognitive disorders, such as those caused by alzheimer's disease.

Description

Co-agonists of GLP-1 and the amylin receptor The present application is a divisional application of patent application with the application number 202180085551.0, the application day 2021, 12 months 17, and the name "co-agonist of GLP-1 and amylin receptor". Technical Field The present invention relates to compounds comprising a GLP-1 receptor agonist and an amylin receptor agonist. The invention also relates to pharmaceutical formulations suitable for, but not limited to, oral administration comprising such compounds. The compounds and pharmaceutical formulations comprising them are useful in the medical treatment of subjects suffering from overweight or obesity with or without associated co-morbidity, diabetes with or without associated co-morbidity, cardiovascular disease, non-alcoholic steatohepatitis (NASH) and cognitive disorders, such as those caused by alzheimer's disease. Background Overweight and obesity are abnormal or excessive accumulation of body fat that pose a threat to the overall health of the individual. Body Mass Index (BMI) exceeding 25 is considered overweight and BMI exceeding 30 is considered obese. Obesity is a major risk factor for many serious diseases, including type 2 diabetes and its related co-morbidities, and cardiovascular diseases such as heart disease and stroke, which are major causes of global death. Obesity is now recognized by the World Health Organization (WHO) as a problem that has developed to a degree of popularity, even among children, reportedly 19 million adults worldwide in 2016 and children under 3830 ten thousand 5 worldwide in 2019. It is stated by WHO that 4.22 million people worldwide have diabetes and 160 tens of thousands of deaths each year are directly attributable to diabetes. Thus, there is a great incentive for individuals and society to try to prevent and/or treat obesity. Treatment with drugs such as liraglutide, orlistat and naltrexone-bupropion has been shown to result in some weight loss when diet and exercise alone are insufficient to reduce the Body Mass Index (BMI) of obese individuals to acceptable levels. Nevertheless, bariatric surgery has proven necessary in many cases. While bariatric surgery is currently the most effective treatment in achieving long-term weight loss, it is an invasive procedure associated with high risk and high cost to the patient. Thus, an effective and minimally invasive method of treatment would be a significant improvement in the treatment of obesity. Amylin (amyin) is a long polypeptide hormone consisting of 37 amino acids, which is produced in pancreatic beta (β) -cells and is co-secreted with insulin. The half-life of endogenous amylin is about 15-20 minutes. It acts in several different organ systems, mainly through the amylin receptor 1-3 (AMYR 1-3). Amylin is an important regulator of energy metabolism in health and disease, inhibits glucagon secretion, delays gastric emptying, signals satiety, and suppresses appetite. Other effects of amylin, such as effects on the cardiovascular system and bones, have also been reported. Clinical studies have shown that amylin receptor agonists are useful in the treatment of overweight, obesity, type 1 diabetes and/or type 2 diabetes. Currently, there is a product (Symlin) on the market containing an amylin receptor agonist (pramlintide acetate) as an active pharmaceutical ingredient. Symlin is a liquid pharmaceutical formulation for subcutaneous administration, and has been approved for use in type 1 or type 2 diabetics who use basal insulin and prandial insulin and who have failed to achieve the desired glycemic control despite optimal insulin therapy. Pramlintide (PRAMLINTIDE) for overweight and obese patients is also being studied clinically. Pramlintide has a short biological half-life (less than 1 hour) and requires three daily administrations. Thus, there is a great diurnal variation in plasma levels of pramlintide in patients treated therewith. GLP-1 is a polypeptide hormone consisting of 30 or 31 amino acids, synthesized and secreted by enteroendocrine L-cells. GLP-1 is an incretin that reduces blood glucose levels in a glucose-dependent manner by enhancing insulin secretion. Endogenous GLP-1 is rapidly degraded mainly by dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of about 2 minutes. Several marketed products containing GLP-1 receptor agonists as active pharmaceutical ingredient have been batched for individuals suffering from type 2 diabetes. The pharmaceutical composition comprises dolapride (dulaglutide) (Trulicity), exenatide (Byetta, bydureon), liraglutide (liraglutide) (Victoza), liraglutide (lixisenatide) (Lyxumia) and semraglutide (semaglutide) (Ozempic). The first GLP-1 receptor agonist (Rybelsus) to be obtained as a tablet. It is safe and effective as monotherapy and in addition to drug therapy for the treatment of type 2 diabetes. Two marketed products containing GLP-1 receptor agonists as active pharmaceutical ingredient are approved for