Development of PDE3 Inhibitors for Cardiovascular Diseases

Phosphodiesterase 3 (PDE3) inhibitors block the degradation of cAMP, leading to elevated intracellular cAMP levels and resulting in positive inotropic (increased myocardial contractility) and vasodilatory effects. As a trusted partner in cardiovascular drug development, Ace Therapeutics offers expert preclinical evaluation services to accelerate the development of novel PDE3 inhibitors.

The Role of PDE3 in Cardiovascular Diseases

PDE3 is highly expressed in the heart, vascular smooth muscle, and platelets, where it regulates cellular functions by degrading cyclic adenosine monophosphate (cAMP). Given its central role in regulating cAMP levels, a key mediator of cardiovascular function, PDE3 is a promising target for novel cardiovascular therapies. PDE3 inhibitors elevate cAMP levels in cardiac cells, activating protein kinase A (PKA) and enhancing myocardial contractility. In vascular smooth muscle cells, increased cAMP levels induce vasodilation, reduce peripheral resistance, decrease cardiac load, and alleviate symptoms in heart failure patients.

Fig. 1 Mechanisms of action of cilostazol (a phosphodiesterase-3 inhibitor). (Sohn M, Lim S, 2024)

Discovery of PDE3 Inhibitors

• Small Molecule PDE3 Selective Inhibitors
  We offer comprehensive research services including small molecule high-throughput screening, lead compound optimization, and preclinical pharmacodynamic studies to assist clients in developing highly selective, long-acting PDE3 inhibitors for the treatment of acute heart failure and cardiogenic shock.

In Vitro Pharmacodynamic Studies

• Enzyme Activity Assay
  The inhibitory activity (IC₅₀) of drug candidates against PDE3 is measured using fluorescent substrates or colorimetric assays, with selectivity assessed across PDE isoforms such as PDE3A and PDE3B.
• cAMP Levels Measurement
  Changes in intracellular cAMP levels are detected via ELISA or fluorescence resonance energy transfer (FRET), aiding in the mechanistic characterization of PDE3 inhibitors.
• In Vitro Evaluation in PDE3-Expressing Cell Lines
  High PDE3-expressing cell lines, including cardiomyocytes and vascular smooth muscle cells, are used to evaluate the potency and efficacy of drug candidates.

In Vivo Pharmacodynamic Studies

• Effects on Heart Failure
  We provide customized animal models of heart failure, such as coronary artery ligation-induced heart failure models, to assess the effects of drugs on improving cardiac function.
• Effects on Pulmonary Hypertension
  We offer specialized animal models of pulmonary hypertension, such as monocrotaline-induced pulmonary hypertension models, to evaluate the ability of drug candidates to reduce pulmonary vascular resistance.
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• Effects on Myocardial Ischemia
  We develop customized myocardial ischemia models, including ischemia-reperfusion injury models, to evaluate the cardioprotective effects of drug candidates.

Leveraging our research expertise in the cardiovascular field, Ace Therapeutics provides integrated R&D services that accelerate the development of next-generation PDE3 inhibitors. If you are interested in our services, please do not hesitate to contact us.

1. Sohn, M.; Lim, S. The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis. Int J Mol Sci. 2024, 25(5):2593.