Method and compositions for increasing the serum half-life of pharmacologically active agents by binding to transthyretin-selective ligands
First Claim
1. A pharmaceutical composition comprising a covalent conjugate of a pharmacologically active agent and a transthyretin-selective ligand whose binding affinities for thyroid-binding globulin and thyroid hormone receptor are each less than about 1% that of the binding affinity of said ligand for transthyretin, wherein the transthyretin-selective ligand is selected from the group consisting of the following structural formulae (l), (II) and (IV):
- ##STR25## wherein;
n is 0 or 1;
X is NH, O or lower alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, hydroxyl, carboxyl, halogen, amino, lower alkyl-substituted secondary amino, and lower alkyl-disubstituted tertiary amino and, if lower alkylene, optionally containing 1 to 4 --O--, --NH--, --CONH-- or --(CO)-- linkages;
R1, R2, R3, R4, R5, R6, and R11 are selected from the group consisting of hydrogen, halogen, halogen-substituted lower alkyl, hydroxyl, lower alkyl, cyano, --(CH2)m CHO, --(CH2)m OH, --(CH2)m COOR13, and --(CH2)m CONHR14 wherein m is 0 or 1, R13 is hydrogen or C1 -C12 alkyl, C1 -C12 alkenyl or C1 -C12 alkynyl, and, when R13 is other than hydrogen, it is optionally substituted with 1 to 8 substituents selected from the group consisting of hydroxyl, carboxyl, lower alkyl, halogen and amino, and further optionally contains 1 to 8 --O--, --NH--, or --(CO)-- linkages, and R14 is hydrogen or lower alkyl, with the proviso that at least one of R1, R2 and R3, and at least one of R4, R5 and R6 is hydroxyl or --(CH2)m COOH; and
R12 is hydrogen or lower alkyl.
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Abstract
Compositions and methods are provided for increasing the serum half-life of a pharmacologically active agent. The novel compositions are covalent conjugates of the selected pharmacologically active agent and a transthyretin-binding ligand such as tetraiiodothyroacetic acid, 2,4,6-triiodophenol, flufenamic acid, or the like.
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Citations
27 Claims
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1. A pharmaceutical composition comprising a covalent conjugate of a pharmacologically active agent and a transthyretin-selective ligand whose binding affinities for thyroid-binding globulin and thyroid hormone receptor are each less than about 1% that of the binding affinity of said ligand for transthyretin, wherein the transthyretin-selective ligand is selected from the group consisting of the following structural formulae (l), (II) and (IV):
- ##STR25## wherein;
n is 0 or 1;X is NH, O or lower alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, hydroxyl, carboxyl, halogen, amino, lower alkyl-substituted secondary amino, and lower alkyl-disubstituted tertiary amino and, if lower alkylene, optionally containing 1 to 4 --O--, --NH--, --CONH-- or --(CO)-- linkages; R1, R2, R3, R4, R5, R6, and R11 are selected from the group consisting of hydrogen, halogen, halogen-substituted lower alkyl, hydroxyl, lower alkyl, cyano, --(CH2)m CHO, --(CH2)m OH, --(CH2)m COOR13, and --(CH2)m CONHR14 wherein m is 0 or 1, R13 is hydrogen or C1 -C12 alkyl, C1 -C12 alkenyl or C1 -C12 alkynyl, and, when R13 is other than hydrogen, it is optionally substituted with 1 to 8 substituents selected from the group consisting of hydroxyl, carboxyl, lower alkyl, halogen and amino, and further optionally contains 1 to 8 --O--, --NH--, or --(CO)-- linkages, and R14 is hydrogen or lower alkyl, with the proviso that at least one of R1, R2 and R3, and at least one of R4, R5 and R6 is hydroxyl or --(CH2)m COOH; and R12 is hydrogen or lower alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- ##STR25## wherein;
- 14. A method for extending the half-life of a pharmacologically active agent containing a functional group not essential for pharmacological activity, comprising covalently binding said agent, through said functional group, to a transthyretin-selective ligand whose binding affinities for thyroid-binding globulin and thyroid hormone receptor are each less than about 1% that of the binding affinity of said ligand for transthyretin.
Specification