Prodrug compounds with isoleucine

• US 20070020694A1
• Filed: 09/29/2006
• Published: 01/25/2007
• Est. Priority Date: 06/14/2000
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: Gangwar, Sanjeev, Yarranton, Geoffrey, Pickford, Lesley, Nieder, Matthew, Lobl, Thomas
• Granted Patent: US 7,329,507 B2
• Time in Patent Office: Days
• US Class Current: 435/7.100
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• 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: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic

Abstract

The compounds of the invention are modified forms of therapeutic agents. A typical prodrug compound of the invention comprises a therapeutic agent, an oligopeptide having an isoleucine residue, a stabilizing group and, optionally, a linker group. The prodrug is cleavable by an enzyme associated with the target cell. Methods of making and using the compounds are also disclosed.

Claims

1. A method of designing a prodrug for administration to a patient, the method comprising:

(1) identifying an oligopeptide of the formula (AA)_n-AA³-AA²-AA¹, wherein;

each AA independently represents an amino acid,

n is 0 or 1, and when n is 1, then (AA)_n is AA⁴ which represents any amino acid, AA³ represents isoleucine, AA² represents any amino acid, and AA¹ represents any amino acid,

(2) linking the oligopeptide at a first attachment site of the oligopeptide to a stabilizing group, and

(3) directly or indirectly linking the oligopeptide to a therapeutic agent at a second attachment site of the oligopeptide,

wherein steps (2) and (3) may be performed in any order or concurrently and further wherein a conjugate is formed by performance of steps (1) through (3),

(4) testing if the conjugate is cleavable by TOP, (5) testing if the conjugate is stable in whole blood, and (6) selecting the conjugate as a prodrug if the conjugate is resistant to cleavage by TOP and stable in whole blood.

2. The method of claim 1, wherein the first attachment site is the N-terminus of the oligopeptide.

3. The method of claim 1, wherein the second attachment site is the C-terminus of the oligopeptide.

4. The method of claim 1, wherein the first attachment site is the C-terminus of the oligopeptide.

5. The method of claim 1, wherein the second attachment site is the N-terminus of the oligopeptide.