Hiv Prodrugs Cleavable by Cd26

a technology of prodrug and cd26, which is applied in the field of prodrug of hiv inhibitory compounds, can solve the problems of unsatisfactory physicochemical and biopharmaceutical properties of many existing drug molecules already on the market, unrealized medical advances, and unfavorable new chemical structures. , to achieve the effect of convenient preparation, and reducing the risk of infection
US20080214648A1Inactive Publication Date: 2008-09-04DE KOCK HERMAN AUGUSTINUS +2
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Patent Information

Authority / Receiving Office
US · United States
Patent Type
Applications(United States)
Current Assignee / Owner
DE KOCK HERMAN AUGUSTINUS
Publication Date
2008-09-04
Estimated Expiration
Not applicable · inactive patent

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Abstract

The present invention provides new prodrugs which are conjugates of a therapeutic compound and a peptide wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present prodrugs have the formulathe stereoisomeric forms and salts thereof, wherein n is 1 to 5; Y is proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine; X is selected from any amino acid in the D- or L-configuration; X and Y in each repeat of [Y-X] are chosen independently from one another and independently from other repeats; Z is a direct bond or a bivalent straight or branched saturated hydrocarbon group having from 1 to 4 carbon atoms; R1 is an aryl, heteroaryl, aryloxy, heteroaryloxy, aryloxyC1-4alkyl, heterocycloalkyloxy, heterocycloalkylC1-4alkyloxy, heteroaryloxyC1-4alkyl, heteroarylC1-4alkyloxy; R2 is arylC1-4alkyl; R3 is C1-10alkyl, C2-6alkenyl or C3-7cycloalkylC1-4alkyl; R4 is hydrogen or C1-4alkyl. The present invention furthermore provides the use of said prodrugs as medicines as well as a method of producing said prodrugs.
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Description

FIELD OF THE INVENTION

[0001] The invention relates to prodrug of HIV inhibitory compounds whereby the HIV inhibitory compound is released or activated by proteolysis of a peptidic moiety. The invention also relates to methods for increasing oral uptake, modify serum protein binding, blood-brain barrier penetration or solubility and bioavailability of the HIV inhibitory compounds.BACKGROUND OF THE INVENTION

[0002] Modern drug discovery techniques (e.g. combinatorial chemistry, high-throughput pharmacological screening, structure-based drug design) are providing very specific and potent drug molecules. However, it is rather common that these novel chemical structures have unfavourable physicochemical and biopharmaceutical properties. Besides, during the development of new therapeutic agents, researchers typically focus on pharmacological and / or biological properties, with less concern for physicochemical properties. However, the physicochemical properties (dissociation constant, solubili...

Claims

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