Moexipril Hydrochloride

Moexipril hydrochloride is a prodrug that is hydrolyzed in the liver to its active metabolite moexiprilat, which inhibits angiotensin-converting enzyme (ACE) both in plasma and at the tissue level. In spontaneously hypertensive rats treated intragastrically for six days with 2 mg/kg moexipril, plasma ACE activity was inhibited by 87 percent, while tissue ACE inhibition reached 92 percent in lung, 26 percent in myocardium, 21 percent in kidney and 39 percent in aorta, with no significant inhibition in skeletal muscle. Moexipril treatment also induced a significant increase in cardiac homogenate levels of 6-keto-PGF1α, an index of prostacyclin (PGI2) generation. In vitro incubation experiments confirmed that the differential tissue ACE inhibition was not primarily dependent on drug availability in each organ but rather on intrinsic tissue susceptibility.

Fig. 1 Effects of a 6-day in vivo treatment with Moexipril on ACE-activity. (Torsello A.; et al. 2003)

Moexipril was identified through high-throughput computational screening as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4). Biochemical assays confirmed that moexipril inhibited PDE4 activity in the micromolar range. Using a FRET-based EPAC1 biosensor, moexipril was shown to markedly potentiate forskolin-induced elevation of intracellular cAMP levels. Functional studies demonstrated that the PDE4 inhibitory effect of moexipril led to PKA-dependent phosphorylation of the small heat shock protein Hsp20. This study revealed that moexipril possesses PDE4 inhibitory activity in addition to its established ACE inhibition, suggesting potential for development of better-tolerated PDE4 inhibitors with an improved therapeutic window for inflammatory diseases.

Fig. 2 Change in FRET ratio triggered by FSK, followed by treatment with Moexipril. (Cameron R T.; et al. 2013)