S-7d

S-7d is a highly selective, small molecule allosteric inhibitor of **phosphodiesterase-5 (PDE5)**, derived from the natural product evodiamine (EVO). Unlike traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil, which bind to the orthosteric active site, S-7d and its analogs target a unique allosteric pocket. Binding to this pocket induces a dramatic conformational change in the H-loop of the PDE5 enzyme (with movements up to 24 Å), which sterically blocks the binding of substrates or other inhibitors to the active site. This novel mechanism allows S-7d to achieve exceptional selectivity (>570-fold) over related isoforms such as PDE6C and PDE11A, potentially minimizing side effects like visual disturbances or muscle pain associated with off-target inhibition. Preclinical studies have demonstrated that S-7d is effective in treating pulmonary hypertension in vivo.

Other names

(S)-7d