Depsipeptide and congeners thereof for use as immunosuppressants
AssigneeXCYTE Therapies, Inc.
InventorSøren Skov
Life of this patent
Estimating the term…
Abstract
Depsipeptides and congeners thereof are disclosed having the following structure: wherein m, n, p, q, X, R1, R2 and R3 are as defined herein. These compounds, including FR901228, have activity as, for example, immunosuppressants, as well as for the prevention or treatment of patients suffering or at risk of suffering from inflammatory, autoimmune or immune system-related diseases including graft-versus-host disease and enhancement of graft/tissue survival following transplant. Also provided are methods for inhibiting lymphocyte activation, proliferation, and/or suppression of IL-2 secretion.
Claims40
A compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomers thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety;
- with the proviso that the compound is not FR901228.
A method of preventing or suppressing an immune response or immune mediated response of an animal, comprising administering to said animal an effective amount of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for inhibiting the proliferation of lymphocytes, comprising administering to an animal an effective amount of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for enhancing graft survival following transplant, comprising administering to an animal previous to, concurrently with, or subsequent to a transplant procedure an effective amount of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for reducing interleukin-2 secretion from lymphocytes, comprising administering to an animal an effective amount of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for inhibiting induction of CD25 or CD154 on lymphocytes following lymphocyte stimulation, comprising administering to an animal an effective amount of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for inducing anergy or apoptosis in activated T-cells while maintaining overall T-cell counts, comprising administering to an animal a dosage of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for inducing immune system tolerance to an antigen, comprising administering to an animal a dosage of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
A method for reducing secretion of tumor necrosis factor-alpha, comprising administering to an animal a dosage of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl aryl or arylalkyl moiety.
A method for inhibiting the cell cycle of an activated T-cell prior to S-phase entry, comprising administering to an animal a dosage of a compound having the following structure:
- or a pharmaceutically acceptable salt or stereoisomer thereof,
- wherein
- m is 1, 2, 3 or 4;
- n is 0, 1, 2 or 3;
- p and q are independently 1 or 2;
- X is O, NH or NR;
- R1, R2 and R3 are the same or different and independently an amino acid side-chain moiety or an amino acid side-chain derivative;
- and
- R is a lower chain alkyl, aryl or arylalkyl moiety.
Dependencies are inferred from the claim text.