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• W2355460806 abstract "The endogenous peptides angiotensin II (Ang II) and endothelin-1 (ET-1) are powerful vasoconstrictors and mitogens and both peptides have been implicated in the pathogenesis of hypertension and other related disorders. Studies in animal models have demonstrated that simultaneous blockade of angiotensin type 1 (AT1) and endothelin type A (ETA) receptors produced greater therapeutic benefits than antagonizing either AT1 or ETA receptors alone. Merging together, by rational design, the structural features of the AT1 receptor antagonist irbesartan with key structural elements in a biphenylsulfonamide ETA receptor antagonist (BMS-193884) followed by additional optimization provided compound 8 (BMS-346567) as a dual action receptor antagonist (DARA), which potently blocked both AT1 and ETA receptors. In rats, DARA 8 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than either AT1 or ETA receptor antagonists alone. DARA 8 clearly demonstrated superiority over irbesartan (an AT1 receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT1 and ETA receptor blockade in a single molecule. In phase I and phase II clinical trials, DARA 8 was found to be safe and well tolerated and demonstrated statistically significant greater reductions in blood pressure than placebo in hypertensive patients. Overall, these preclinical and clinical data demonstrate that the DARA mechanism has the potential to be a significant new addition to the armamentarium of anti-hypertensive drugs." @default.
• W2355460806 created "2016-06-24" @default.
• W2355460806 creator A5062259326 @default.
• W2355460806 date "2012-04-12" @default.
• W2355460806 modified "2023-09-24" @default.
• W2355460806 title "Designing Drugs with Dual Activity: Novel Dual Angiotensin II and Endothelin Receptor Antagonists" @default.
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• W2355460806 doi "https://doi.org/10.1039/9781849734912-00316" @default.
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