MI, known more commonly as a heart attack, is estimated to account for approximately 280,000 out-of-hospital deaths each year in the United States. Most of these events are preceded by warning symptoms such as angina (chest pain) or dyspnea (shortness of breath) that alert patients and others to the need for care. Patients typically present these warning symptoms 30 to 120 minutes prior to MI, providing a limited window of time for medical treatment that could lessen the severity of MI or prevent it entirely.
Scientific Synopsis
After warning symptoms present, several treatments that reduce the rate of disease and prevent MI-related death and the CHF that often develops post-MI may be administered. Of these, platelet integrin aIIbb3 antagonists can often produce dramatic benefits. Unfortunately, existing aIIbb3 antagonists all require intravenous (IV) administration, making them difficult to deliver in out-of-hospital, emergency-type settings. Additionally, some aIIbb3 antagonists have been shown to induce an undesired conformational change in the integrin receptor that “primes” the receptor to bind fibrinogen, and they may contribute to thrombocytopenia, a condition where the blood platelet count becomes too low.
The goal of this project is to develop a novel aIIbb3 antagonist with properties that would allow it to be delivered more conveniently by auto-injection, the same technology used in EpiPens® and similar devices. By greatly improving the convenience of aIIbb3 antagonist delivery, the project team believes that the use of these agents in out-of-hospital settings would increase, thereby leading to a reduction in disease and death from MI and CHF. If such an agent bound the integrin receptor without inducing an undesired conformational change, the risk of thrombocytopenia should also be diminished.
Medicinal chemistry efforts in the team’s laboratories have led to the discovery of lead compound RUC-4, a potent aIIbb3 antagonist with properties suitable for delivery by auto-injection. The project team initially identified the chemical starting point RUC-1 from high-throughput screening. Structure-guided optimization of that compound ultimately produced RUC-4, a potent aIIbb3 antagonist that binds integrin without inducing undesired conformational change. Importantly, RUC-4 displays high aqueous (water) solubility (>60 mg/mL) as well as other properties that should permit delivery by auto-injection. In a cell-based assay, RUC-4 potently and selectively inhibits the binding of fibrinogen to aIIbb3. In a mouse model of arterial thrombosis, RUC-4 produces a significant decrease in arterial occlusion compared with the vehicle. Current efforts are aimed at optimizing the salt form and formulation of RUC-4 to enable its advancement into clinical trials as a treatment for MI.
This figure illustrates the chemical starting point, RUC-1, and optimized compound RUC-4. The bar graph in the center indicates the effect of RUC-4 on the binding of aIIbb3 (in red on the left) to fibrinogen and on the binding of aVb3 (in blue on right) to vitronectin, compared with control and several other agents. The line graph on the right indicates the effect of RUC-4 on arterial thrombosis induced by laser injury in mice, with the lines indicating the percentage of mice free from arterial occlusion after treatment with the vehicle (blue line on left) or RUC-4 (red line on the right). (Reprinted with permission from Li J, et al. A novel aIIbb3 antagonist for pre-hospital therapy of myocardial infarction. Arterioscl Thromb Vasc Biol. 2014;34(10):2321–9. Copyright 2014 Arteriosclerosis, Thrombosis, and Vascular Biology.)
Lead Collaborators
- Craig J. Thomas, Ph.D., NCATS, NIH
- Jian-kang Jiang, Ph.D., NCATS, NIH
- Barry Coller, M.D., Rockefeller University
Publications
- Li J, Vootukuri S, Shang Y, Negri A, Jiang J-k, Nedelman M, Diacova TG, Filizola M, Thomas CJ, Coller BS. RUC-4: A novel aIIbb3 antagonist for pre-hospital therapy of myocardial infarction. Arterioscl Thromb Vasc Biol. 2014;34(10):2321–9.
- Jiang J-k, McCoy JG, Shen M, LeClair CA, Huang W, Negri A, Li J, Blue R, Harrington AW, Naini S, David G III, Choi W-S, Volpi E, Fernandez J, Babayeva M, Nedelman MA, Filizola M, Coller BS, Thomas CJ. A novel class of ion displacement ligands as antagonists of the aIIbb3 receptor that limit conformational reorganization of the receptor. Bioorg Med Chem Lett. 2014;24(4):1148–54.
- Zhu J, Choi W-S, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Structure-guided design of a high-affinity platelet integrin aIIbb3 receptor antagonist that disrupts Mg2+ binding to the MIDAS. Sci Trans Med. 2012;4(125):125ra32.
Public Health Impact
This project has yielded the optimized aIIbb3 antagonist RUC-4. This compound displays high water solubility across a range of pHs, and an overall profile that facilitates delivery by auto-injection in out-of-hospital settings. Current work is aimed at further optimizing RUC-4 to enable its advancement into human clinical trials as a treatment for MI.