1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities

To discover new multifunctional agents for the treatment
of cardiovascular
diseases, we designed and synthesized a series of compounds with a
cyclopropyl alcohol moiety and evaluated them in biochemical assays.
Biological screening identified derivatives with dual activity: preventing
Ca2+ leak through ryanodine receptor 2 (RyR2) and enhancing
cardiac sarco-endoplasmic reticulum (SR) Ca2+ load by activation
of Ca2+-dependent ATPase 2a (SERCA2a). The compounds that
stabilize RyR2 at micro- and nanomolar concentrations are either structurally
related to RyR-stabilizing drugs or Rycals or have structures similar
to them. The novel compounds also demonstrate a good ability to increase
ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes,
e.g., the half-maximal effective concentration (EC50) was
as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with
two cyclopropanol groups. Our findings indicate that these derivatives
can be considered as new lead compounds to improve cardiac function
in heart failure.