PDE5-IN-1

PDE5-IN-1 (compound 2) is a PDE5 inhibitor with an IC50 of 5.6 nM and demonstrates oral bioavailability. It forms a hydrogen bond interaction with the Q817 residue and an aromatic π-π stacking interaction with the F820 residue in the PDE5 catalytic domain. Additionally, PDE5-IN-1 exhibits anti-myocardial hypertrophy and vasodilation effects, reducing mean pulmonary arterial pressure and right ventricular hypertrophy index. This compound is useful in pulmonary hypertension research.

PDE5-IN-1 (compound 2) (at multiple concentrations; incubation for 15 minutes) can strongly inhibit the catalytic domain of PDE5A, with an IC50 of 5.6 nM; it shows significant selectivity compared to other PDE families, with the selectivity index ranging from 10 (relative to PDE6A) to >1700 (relative to PDE1B, PDE3A, PDE7A1, PDE9A2). PDE5-IN-1 (at multiple concentrations) has a relatively weak overall inhibitory effect on human major liver CYP isoforms, showing only moderate inhibition on CYP1A2 (IC50 = 7.6 μM), and no significant inhibition on the other six key isoforms; it also shows only a weak inhibitory effect on the hERG potassium channel, with an IC50 > 10 μM. PDE5-IN-1 (0.5 μM; incubated to determine T1/2) shows stability in both rat and human liver microsomes, with a half-life significantly longer than the positive control midazolam.

PDE5-IN-1 (compound 2), administered at 5.0 mg/kg via gavage once daily for three consecutive weeks, significantly reduces mean pulmonary arterial pressure (mPAP) and right ventricular hypertrophy index (RVHI) in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT), demonstrating superior efficacy compared to 10.0 mg/kg of sildenafil citrate.