Reducing platelet activation, aggregation and platelet-stimulated thrombosis or blood coagulation by reducing mitochondrial respiration

Patent metadata

Field	Value
Publication number	US-9918964-B2
Application number	US-201113093825-A
Country	US
Kind code	B2
Filing date	Apr 25, 2011
Priority date	Apr 23, 2010
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

It has been discovered that inhibiting mitochondrial respiration in platelets reduces platelet activation or platelet aggregation. Certain heterocyclic compounds significantly reduced one or more platelet functions including clumping, sticking or platelet-stimulated clotting. Thus diseases or disorders mediated by inappropriately high levels of platelet activation or platelet aggregation can be treated by administering a therapeutically effective amount of a heterocyclic compound or nonheterocyclic mitochondrial inhibitor that significantly reduces one or more platelet functions including clumping, sticking or platelet-stimulated clotting, preferably in a reversible manner.

First claim

What is claimed is:

1. A method of reducing platelet activation in a human subject having an inappropriately high level of platelet activation, comprising a step of administering to the subject a pharmaceutical formulation comprising an effective amount of a tetrazole or triazole compound selected from the group consisting of: 1H-tetrazol-5-amine, 4,5-dibromo-1H-1,2,3 triazole, 5-(2H-tetrazol-5-ylmethyl)-2H-tetrazole, 2H-tetrazole-5-carboxamide, 5-(2H-tetrazol-5-yl)-2H-tetrazole, ethyl 2-(1H-tetrazol-5-yl)acetate, and 5-methylsulfanyl-1H-tetrazole,
or a pharmaceutically acceptable salt thereof, whereby platelet activation in the subject is reduced.

2. The method of claim 1 , further comprising a step of determining an inappropriately high level of platelet activation by an in vitro assay of the subject's platelet function, said assay comprising at least one of clumping, clotting, and sticking.

3. The method of claim 1 , wherein the compound is selected from the group consisting of: 1H-tetrazol-5-amine, 4,5-dibromo-1H-1,2,3 triazole, and 5-methylsulfanyl-1H-tetrazole.

4. The method of claim 3 , further comprising a step of determining an inappropriately high level of platelet activation by an in vitro assay of the subject's platelet function, said assay comprising at least one of clumping, clotting, and sticking.

5. The method of claim 1 , wherein the compound is selected from the group consisting of: 1H-tetrazol-5-amine, 5-(2H-tetrazol-5-ylmethyl)-2H-tetrazole, 2H-tetrazole-5-carboxamide, 5-(2H-tetrazol-5-yl)-2H-tetrazole, ethyl 2-(1H-tetrazol-5-yl)acetate, and 5-methylsulfanyl-1H-tetrazole.

6. The method of claim 5 , further comprising a step of determining an inappropriately high level of platelet activation by an in vitro assay of the subject's platelet function, said assay comprising at least one of clumping, clotting, and sticking.

Assignees

• Collman James P
• Herrmann Paul Clifford
• Tyvoll David Alvin
• Decreau Richard
• Bull Brian Stanley
• Barile Christopher Jeffrey
• Univ Leland Stanford Junior

Inventors

• Collman James P
• Herrmann Paul Clifford
• Tyvoll David Alvin
• Decreau Richard
• Bull Brian Stanley
• Barile Christopher Jeffrey

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title