Peptide-peptidase inhibitor conjugates and methods of using same

• US 8,759,295 B2
• Filed: 05/21/2010
• Issued: 06/24/2014
• Est. Priority Date: 03/21/2006
• Status: Expired due to Fees

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC), Amylin Pharmaceuticals LLC (Bristol-Myers Squibb Company)
• Inventors: Ghosh, Soumitra S., Alfaro-Lopez, Josue, D'Souza, Lawrence J., Levy, Odile Esther, Lin, Qing, Soares, Christopher J.
• Primary Examiner(s): HOWARD, ZACHARY C
• Application Number:
  US12/785,396
• Publication Number:
  US 20100292172A1
• Time in Patent Office: 1,495 Days
• Field of Search: None
• US Class Current: 514/16.2
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

Peptide-peptidase inhibitor conjugate molecules are disclosed. These conjugate molecules are useful as agents for the treatment and prevention of metabolic and cardiovascular diseases, disorders, and conditions. Such diseases, conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin-resistance, obesity, and diabetes mellitus of any kind, and other diabetes-related disorders.

Claims

1. A peptide-peptidase inhibitor conjugate comprising a peptide covalently linked to a peptidase inhibitor, wherein the peptide comprises exendin-3, exendin-4, or an exendin analog comprising the sequence set forth in any one of SEQ ID NOs:

65-71 and 73, wherein the peptidase inhibitor comprises an angiotensin-converting enzyme inhibitor, and wherein the peptide-peptidase inhibitor conjugate is synthesized chemically or recombinantly.

2. The conjugate of claim 1 wherein the plasma half-life of the conjugate is greater than the plasma half-life of the peptide not conjugated to the peptidase inhibitor.

3. A pharmaceutical composition comprising the conjugate of claim 1.

4. A method for treating a metabolic disease or a cardiovascular disease in a subject in need thereof comprising administering a therapeutically effective amount of the conjugate of claim 1.

5. A method of decreasing degradation of a peptidase-sensitive peptide in a subject comprising administering a composition comprising the peptide-peptidase inhibitor conjugate compound according to claim 1 to a subject in an amount effective to decrease degradation of a peptidase-sensitive peptide.

6. A method of increasing plasma concentration of a biologically active, peptidase-sensitive peptide in a subject comprising administering a composition comprising the peptide-peptidase inhibitor according to claim 1 to a subject in an amount effective to increase plasma half-life of a biologically active, peptidase-sensitive peptide.