Cytotoxic-drug delivering molecules targeting hiv (cdm-hs), cytotoxic activity against the human immunodeficiency virus and methods of use
AssigneeYale University
InventorsDavid Spiegel, Christopher Parker
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Abstract
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.
Claims47
A CDM-Hs compound according to the general formula:
- Where CYT is a moiety of a cytotoxic agent capable of causing death of a cell into which it is introduced;
- VICB is a virus invasion cell binding moiety comprising a group which is capable of binding to gp120 envelope protein on HIV virus or a cell surface of CD4 cells which are infected with HIV (HIV+) in a patient or subject;
- LL is a labile linker molecule which chemically links CYT to a connector moiety CON in said compound, is optionally linked to [CON] through a second non-labile linker [NLL] and is labile when said compound enters a cell;
- NLL is a non-labile linker molecule which chemically links VICB to CON in a molecule;
- CON is a bond or a connector molecule which links LL or NLL to CYT and/or VICB;
- Each j is independently 0, 1, 2, 3, 4 or 5;
- Each k is independently 0, 1, 2, 3, 4 or 5, with the proviso that k and/or j is at least 1 when CON is a bond;
- Each m in a molecule is independently an integer from 1 to 25;
- Each n in a molecule is independently an integer from 1 to 15,
- or a pharmaceutically acceptable salt, stereoisiomer, solvate or polymorph thereof.
A compound according to the chemical structure:
- Where n and n′ are each independently 2-8;
- i is 0 or 1;
- [LL] is a labile linker according to the chemical structure:
- where R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10;
- X is O, N—RAL or S;
- RAL is H or a C1-C3 alkyl group;
- Y is O or S and
- Z=Me, Et, iPr, tBu, Ph, each of which may be optionally substituted with one or more halogen groups and where said Ph group may be further optionally substituted with OMe or a C1-C3 alkyl group which itself may be substituted with up to three halogens;
- or
- [LL] is a group according to the chemical formula:
- and
- R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10;
- or [LL] is an enzymatically cleaved labile linkers include those according to the chemical structure:
- Where the protease (cathepsin) substrate is a peptide containing from 2 to 50 amino acid units, and
- R is an ethylene glycol group, or a methylene group;
- and n is from 0 to 10;
- or
- [LL] is a group according to the chemical structure:
- Where the points of attachment in each of the labile linkers as indicated are joined to other portions of the molecule as indicated;
- [NLL] when present is a non-labile linker (poly)ethylene glycol linker of from 2 to 8 ethylene glycol units, or [NLL] is a group:
- where each XS is independently S, O or N—RS, preferably S;
- RS is H or C1-3 alkyl, preferably H;
- Sc is CH2;
- CH2O;
- or CH2CH2O;
- i is 0 or 1;
- and
- mS is 0, 1, 2, 3, 4, 5, or 6;
- and
- [CYT] is a group according to the chemical structure:
- wherein X is a group which binds said CYT moiety to said labile linker,
- where R1N is H or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups (most often H) and the symbol signifies a chemical attachment point of the cytotoxic moiety to a labile linker, which optionally can be linked through X,
- or a pharmaceutically acceptable salt, stereoisiomer, solvate or polymorph thereof.
A compound according to the chemical structure:
- or the free amine or alternative pharmaceutical salt thereof.
47-51. (canceled)
Dependencies are inferred from the claim text.