Neorx Corporation

Poniard Pharmaceuticals, Inc.

Noerx Corporation

James C Metcalfe

David John Grainger

Peter L Weissberg

Lawrence L Kunz

Sudhakar Kasina

John M Reno

Richard A Klein

Robert W Schroff

Peter G Anderson

The invention provides a method of treating a mammal having, or at risk of, an indication associated with a TGF-beta deficiency comprising administering one or more agents that is effective to elevate the level of TGF-beta. The invention also provides novel compounds that elevate TGF-beta levels, as well as pharmaceutical compositions comprising compounds that elevate TGF-beta levels, and methods for detecting diseases associated with endothelial cell activation.

Compounds and therapies for the prevention of vascular and non-vascular pathologies

A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (I):

Prevention and treatment of cardiovascular pathologies

Prevention and treatment of cardiovascular pathologies with tamoxifen analogues

TGF-beta activators and TGF-beta production stimulators are employed to maintain or increase vessel lumen diameter in a diseased or injured vessel of a mammal. Conditions such as restenosis following angioplasty, vascular bypass grafts, transplanted organs, atherosclerosis or hypertension are characterized by a reduced vessel lumen diameter. In a preferred embodiment of the invention, TGF-beta activators and production stimulators inhibit abnormal proliferation of smooth muscle cells. TGF-beta activators or production stimulators that are not characterized by an undesirable systemic toxicity profile at a prophylactic dose are also amenable to chronic use for prophylactic purposes with respect to disease states involving proliferation and/or migration of vascular smooth muscle cells over time. Further provided is a method for determining TGF-beta in vitro, thereby identifying a patient at risk for atherosclerosis and monitoring a recipient that has received one or more administrations of a TGF-beta activator or production stimulator.

Prevention and treatment of pathologies associated with abnormally

Compounds and therapies for the prevention of vascular and non-vascular

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent. Also discussed are mechanisms for in vivo vascular smooth muscle cell proliferation modulation, agents that impact those mechanisms and protocols for the use of those agents.

Therapeutic inhibitor of vascular smooth muscle cells

TGF-beta activators and TGF-beta production stimulators are employed to prevent or treat conditions characterized by inappropriate proliferation of smooth muscle cells, such as the prevention or reduction of restenosis following angioplasty or other vascular trauma. Such TGF-beta activators and production stimulators inhibit abnormal proliferation of smooth muscle cells. TGF-beta activators or production stimulators that are not characterized by an undesirable systemic toxicity profile at a prophylactic dose are also amenable to chronic use for prophylactic purposes with respect to disease states involving proliferation of vascular smooth muscle cells over time. Further provided is a method for upregulating cellular mRNA coding for TGF-beta.

A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (I): ##STR1## wherein Z is C.dbd.O or a covalent bond; Y is H or O(C.sub.1 -C.sub.4)alkyl, R.sup.1 and R.sup.2 are individually (C.sub.1 -C.sub.4)alkyl or together with N are a saturated heterocyclic group, R.sup.3 is ethyl or chloroethyl, R.sup.4 is H or together with R.sup.3 is --CH.sub.2 --CH.sub.2 -- or --S--, R.sup.5 is I, O(C.sub.1 -C.sub.4)alkyl or H and R.sup.6 is I, O(C.sub.1 -C.sub.4)alkyl or H with the proviso that when R.sup.4, R.sup.5, and R.sup.6 are H, R.sup.3 is not ethyl; or a pharmaceutically acceptable salt thereof, effective to activate or stimulate production of TGF-beta to treat and/or prevent conditions such as atherosclerosis, thrombosis, myocardial infarction, and stroke is provided. Useful compounds include idoxifene and salts thereof. Further provided is a method for identifying a compound that is a TGF-beta activator or production stimulator is provided. Another embodiment of the invention is an assay or kit to determine TGF-beta in vitro. Also provided is a therapeutic method comprising inhibiting smooth muscle cell proliferation associated with procedural vascular trauma employing the administration of tamoxifen or structural analogs thereof, including compounds of formula (I).

Growing community of inventors

Cambridge, United Kingdom

James C Metcalfe