Enalapril Maleate

Enalapril maleate is a prodrug that is hydrolysed after oral administration to enalaprilat, the active angiotensin-converting enzyme inhibitor. Enalaprilat inhibits ACE by binding to the active sites of both its N-domain and C-domain, which are responsible for cleaving angiotensin I into the vasopressor angiotensin II and the antifibrotic peptide Ac-SDKP respectively. The structural and kinetic basis of ACE inhibition by enalaprilat was characterized using X-ray crystallography and fixed-time fluorometric assays. Enalaprilat displayed nanomolar inhibition of both ACE domains, with a Ki value of 3.85 nM for the N-domain and 1.06 nM for the C-domain, corresponding to moderate cACE-selectivity of 3.6-fold. This minimal selectivity is consistent with enalaprilat being a nonselective ACE inhibitor that affects both domains. The binding mode of enalaprilat revealed that it does not extend beyond the S1-S2' subsites in the ACE active site, which limits its ability to achieve higher domain selectivity.

Fig. 1 Crystal structures of nACE in complex with enalaprilat. (Gregory K S.; et al. 2026)

Enalapril maleate nanoproniosomal gels were formulated using lecithin, cholesterol and nonionic surfactants via coacervation phase separation. The gels exhibited good physical characteristics. Ex vivo skin permeation analysis revealed non-Fickian release kinetics and zero-order penetration behaviors with diffusion. One optimized formulation demonstrated approximately 188.99-fold greater bioavailability compared to the marketed Vasotec tablet. In vivo antihypertensive analysis confirmed that the formulation effectively restored elevated rat blood pressures to the normal range. The in vitro-in vivo correlation analysis suggested that ex vivo data could accurately replicate in vivo physiological conditions. Enalapril maleate encapsulated within nanoproniosomal gels can function as controlled drug delivery systems releasing the drug once per day for effective hypertension management.

Fig. 2 SEM image of the optimal formulation EMNP7. (Sabareesh M.; et al. 2024)