Microsomal triglyceride transfer protein

• US 6,492,365 B1
• Filed: 06/07/1995
• Issued: 12/10/2002
• Est. Priority Date: 03/06/1992
• Status: Expired due to Term

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gregg, Richard E., Sharp, Daru Young, Wetterau, John R. II
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US08/486,929
• Time in Patent Office: 2,743 Days
• Field of Search: 514/247, 514/277
• US Class Current: 514/247
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 295/112 with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 14/47 : from mammals
• CPC Class Codes: G01N 2800/044 : Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
• CPC Class Codes: G01N 33/92 : involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

Nucleic acid sequences, particularly DNA sequences, coding for all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, expression vectors containing the DNA sequences, host cells containing the expression vectors, and methods utilizing these materials. The invention also concerns polypeptide molecules comprising all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, and methods for producing these polypeptide molecules. The invention additionally concerns novel methods for preventing, stabilizing or causing regression of atherosclerosis and therapeutic agents having such activity. The invention concerns further novel methods for lowering serum liquid levels and therapeutic agents having such activity.

Claims

1. A method for treating atherosclerosis in a mammalian species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.

3. The method of claim 1 or 2, wherein the agent is a compound of the formula

or a compound of the formula

or a compound of the formula

wherein:

R¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl (all optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl);

R², R³, R⁴ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl;

R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl (all optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl;

with the proviso that when R⁵ is CH₃, R⁶ is not hydrogen,

R⁷ is alkyl (optionally substituted with oxo), aryl, or arylalkyl (wherein the alkyl portion is optionally substituted with oxo).

4. The method of claim 3, wherein the agent is a compound of the formula

or a compound of the formula

wherein:

R¹ is —

R^v—

R^w or

R^v and R^x are each independently alkylene or cis-alkenylene of up to 6 carbon atoms;

R^w is aryl or heteroaryl; and

R^y and R^z are each independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl.

5. The method of claim 4, wherein R^y and R^z are each independently aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

2. A method for decreasing serum lipid levels in a mammalian species, which comprises administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.

6. A method for treating hyperglycemia in a mammalian species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.

7. A method for treating hypertriglyceridemia in a mammalian species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.

8. A method for treating hypercholesterolemia in a mammalian species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.

9. A method for treating hypertriglyceridemia and hypercholesterolemia in a mammalin species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride protein, wherein said agent is not a polynucleotide compound.

10. A method of reducing gastrointestinal triglyceride, fatty acid cholesterol absorption in a mammalian species comprising administration of a therapeutically effective amount of an agent which decreases the amount or activity of microsomal triglyceride transfer protein, wherein said agent is not a polynucleotide compound.