Development of a DHA-Losartan hybrid as a potent inhibitor of multiple pathway-induced platelet aggregation

Abstract

Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the AT₁R blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. In silico studies were first exploited to validate the potential of DHA-L to retain losartan’s ability to bind AT₁R. The antiplatelet activity of DHA-L was evaluated against in vitro platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile.

Communicated by Ramaswamy H. Sarma

GRAPHICAL ABSTRACT

Keywords:

• Losartan
• DHA
• antiplatelet
• cardiovascular diseases
• molecular hybrid
• AT₁R

Acknowledgements

The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the HFRI PhD Fellowship grants (Fellowship Numbers: 14). Last, R. Karpoormath is thankful to the National Research Foundation- South Africa (NRF-SA) and the College of Health Science, University of KwaZulu-Natal, Durban, South Africa.

Disclosure statement

The authors have no conflict of interest to declare.

Additional information

Funding

The project/research is co-financed by the European Regional Development Fund (ERDF) under the Operational Program “Epirus 2014-2020”, NSRF 2014-2020 [Grant Number: 5033143, acronym EP IRUSCOSMECEUT ICALS, to AGT]. The research work was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 991, acronym PROTECT, to AGT). We acknowledge the support of this work by the project “Infrastructure of Microbiome Applications in FoodSystems-FOODBIOMES” (MIS 5047291), which is implemented under the Action “Regional Excellence in R&D Infrastructures”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation”(NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).