Serotonin Reuptake Inhibitors as Novel Anti-Platelet Drugs
The Invention Serotonin-selective reuptake inhibitors (SSRIs) were chemically modified to produce novel quaternary nitrogen derivatives having a peripheral-restricted serotonin reuptake inhibitory activity. The lead compound GR-101 was demonstrated as a novel anti-platelet drug (for reducing platelet aggregation). Such compounds have a clinical potential similarly to aspirin or clopidogrel (Plavix) for reducing the risk of thrombosis and the related risks of ischemia, including ischemic heart disease (IHD), myocardial infarction (MI), cerebral stroke, pulmonary embolism, and type-2 diabetes-associated vascular abnormalities.The novel quaternary SSRIs reduce platelet aggregation via a different mechanism compared with either aspirin or clopidogrel and therefore have a potential as alternatives or add-on therapeutics for reducing platelet aggregation in chronic cardiovascular diseases.
The Need Coronary artery disease (CAD; also called ischemic heart disease), stroke, and pulmonary embolism are cardiovascular diseases which have in common spontaneous formation of small blood clots, unrelated to injury of blood vessels. These small platelet aggregates are carried in the blood stream until they reach small capillaries, where they might cause local ischemia by blocking small capillaries in the heart, lungs or brain tissues. Together, these diseases are the leading cause of mortality and healthcare morbidity in developed countries.
Aspirin, the first synthetic drug ever marketed as a pain-relief and anti-inflammatory drug, has a potential as an anti-platelet agent when given chronically, and therefore can protect from CAD. Another anti-platelet drug, clopidogrel that acts by blocking adenosine receptors on platelets has attained a "blockbuster drug" reputation, with annual sales projected at US$5 billion globally.
However, blocking prostaglandins production by aspirin or ADP receptors by clopidogrel cannot fully protect individuals from increased platelet aggregation, as many additional endogenous modulators are implicated in platelet aggregation during chronic inflammation. Moreover, aspirin is contra-indicated in individuals with ulcers or gastritis due to its tendency to increase gastrointestinal bleeding. Therefore, there is clinical validity to develop additional anti-platelet drugs, as add-on therapy for individuals who receive chronic aspirin, or as replacement for aspirin in individuals in whom aspirin is contra-indicated.
Serotonin (5-HT) is a major CNS neurotransmitter. In addition to its CNS activities, it also has several non-neuronal activities, including cardiovascular modulating effects, potent pro-thrombotic activity and endothelial mitogenic action. Blood platelets are the major storage depot for peripheral 5-HT. Hence, chronically blocking the 5-HT transporter (5-HTT) activity in the periphery by SSRI drugs leads to decreased platelet 5-HT storage capacity, and thereby to reduced biological availability of platelet 5-HT. This in turn is believed to be associated with reduced platelet aggregation during inflammation.
One modality for reducing peripheral 5-HT levels is the chronic use of the antidepressant 5-HT-selective reuptake inhibitor drugs (SSRIs) such as fluoxetine, fluvoxamine, citalopram etc. Indeed, chronic treatment with SSRIs was shown in a large study (1080 MI cases and 4256 controls; 3-year follow-up) to reduce subsequent MI risk by 41%. However, such treatment is reserved in the clinic for affective disorders such as depression and compulsive disorders, and is unwarranted as chronic treatment for people at risk of CAD (or other ischemic diseases). This is mainly due to the undesired side-effects of chronic SSRI treatment, such as flattened emotions, reduced libido and increased aggressiveness. Thus, there is a rational to develop a quaternary SSRI drug, so that it might reduce peripheral 5-HT storage capacity, being an anti-platelet agent, but without entering the CNS and without affecting brain 5-HT mechanisms.
Potential Applications Chronic use for reducing the risk of thrombosis and the related risks of ischemia, including:
• Ischemic heart disease (IHD),
• Myocardial infarction (MI),
• Cerebral stroke (CVA)
• Pulmonary embolism
• Type-2 diabetes-associated vascular abnormalities.
Advantages 1. Novel derivatives of known SSRI 2. Active as anti-platelet agents 3. Different mechanism of action as compared to aspirin or clopidogrel 4. Do not enter the CNS - activity restricted to peripheral tissues.
Stage 1. GR-101 has been synthesized and its purity was verified by HPLC. 2. GR-101 recognized the human platelet 5-HTT and inhibited [3H]5-HT uptake by freshly isolated human platelets with high affinity, thus proving to be a promising anti-platelet agent. 3. GR-101 inhibits human platelet aggregation in-vitro. 4. Direct and indirect in-vivo experiments demonstrated that GR-101 does not penetrate the mouse brain following intra-peritoneal application.
Patent Pending Tech Transfer Officer Dr. Tamar Raz Office: +972-3-6406580 Fax: +972-3-6406675 Mail: [email protected]
Inventor(s): Moshe Rehavi, David Gurwitz
Type of Offer: Licensing
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