BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 1; p. 130732
• Main Authors: Rodríguez, Jessica E., Andrade-Jorge, Erik, Barquet-Nieto, Alina, Estrada-Soto, Samuel E., Gallardo-Ortíz, Itzell A., Villalobos-Molina, Rafael
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2025
• Subjects: Angiotensin converting enzyme; Hypertension; Molecular docking; Spontaneously hypertensive rats; α1D-AR; Hypertension; Spontaneously hypertensive rats; Molecular docking; Angiotensin converting enzyme; α1D-AR
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130732

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications. •The inhibition of the ACE and the antagonism of α1D-ARs ameliorates cardiac function and reverses heart hypertrophy in SHR.•BMY 7378 is a drug with antihypertensive activity avoiding cardiovascular risk in SHR.•BMY 7378 has dual activity: antagonize α1D-ARs and inhibits the angiotensin converting enzyme.•BMY 7378 could be a novel therapeutic tool for the treatment of hypertension and diminish cardiovascular complications.