Table 2 Development of hypoxia signaling-related pharmacological agents: potential therapeutic targets and small molecule candidates
From: Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets
Small molecule drugs/candidates | Categorization (therapeutic target) | Description | Disease | First approval |
|---|---|---|---|---|
Roxadustat (FG-4592, ASP1517, AZD9941) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD1-3), stablization (HIF-1α, HIF-2α) | Anemia, CKD | 2018 in China |
Daprodustat (GSK1278863) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD1-3), stablization (HIF-1α, HIF-2α) | Anemia, CKD | 2020 in Japan |
Vadadustat (MT-6548, AKB-6548) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD3 prefered); stablization (HIF-2α>HIF-1α) | Anemia, CKD | 2020 in Japan |
Enarodustat (JTZ-951) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD1-3); stablization (HIF-1α, HIF-2α) | Anemia, CKD | 2020 in Japan |
Molidustat (BAY 85-3934) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD1-3, particularly PHD3); stablization (HIF-2α, HIF-1α) | Anemia, CKD | 2021 in Japan |
Desidustat (ZYAN1) | Directly (influencing HIF signaling) | HIF-PHI: inhibition (PHD1-3); stablization (HIF-1α, HIF-2α) | Anemia, CKD | 2022 in India |
R59949 | Directly (influencing HIF signaling) | PHD2 activation | PAH | N/A |
2-methoxyestradiol | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
Topotecan | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of mRNA) | PAH | N/A |
Digoxin | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
Anti-CD146 monoclonal antibody, AA98 | Directly (influencing HIF signaling) | HIF-1α inhibition (targeting the upstream molecules) | PAH | N/A |
Caffeic acid phenethyl ester | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
Celastramycin | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
YC-1 | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein buildup and transcriptional activity) | PAH | N/A |
HIF-2α-ASO | Directly (influencing HIF signaling) | HIF-2α inhibition | PAH | N/A |
PT2567 | Directly (influencing HIF signaling) | HIF-2α inhibition (at the level of heterodimerization and DNA binding) | PAH | N/A |
C76 | Directly (influencing HIF signaling) | HIF-2α inhibition (at the level of mRNA) | PAH | N/A |
Apigenin | Directly (influencing HIF signaling) | HIF-1α inhibition (targeting the upstream molecules) | PAH | N/A |
Juglone | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
Resveratrol | Directly (influencing HIF signaling) | HIF-1α inhibition (targeting the upstream molecules) | PAH | N/A |
Astragaloside IV | Directly (influencing HIF signaling) | HIF-1α inhibition (at the level of protein synthesis) | PAH | N/A |
Tagitinin C (1) | Directly (influencing HIF signaling) | HIF-1β inhibition | PAH | N/A |
Luteolin | Directly (influencing HIF signaling) | HIF-2α inhibition (at the level of protein synthesis) | PAH | N/A |
Bevacizumab | Indirectly (VEGF) | Monoclonal antibody targeting VEGF | Cancer, AMD | N/A |
Aflibercept | Indirectly (VEGF) | Fusion protein targeting VEGF | Cancer, AMD | N/A |
Tirapazamine/PR-104A | Indirectly (HAPs) | HAP | Cancer | N/A |
Regadenoson | Indirectly (adenosine receptors) | Adenosine Receptor Agonizts | cardiac imaging | N/A |
Acetazolamide | Indirectly (carbonic Anhydrase) | Carbonic Anhydrase Inhibitor | Altitude Sickness, Edema | N/A |
Nitroglycerin | Indirectly (NO donors) | Promote vasodilation, enhance oxygen supply | Angina | 1879 |
Isosorbide Dinitrate | Indirectly (NO donors) | Promote vasodilation, enhance oxygen supply | Angina | 1962 |
Sodium Nitroprusside | Indirectly (NO donors) | Increased cGMP and vasodilation | Hypertensive emergencies | 1974 |
Sildenafil/Tadalafil | Indirectly (PDE5 inhibitors) | Increased cGMP and vasodilation (sildenafil may also inhibiting HIF-2α and HIF-1β) | PAH | 1998/2013 |
Riociguat | Indirectly (sGC stimulator) | Raising NO levels for vasodilation | PAH | 2013 |
Treprostinil/Epoprostenol/Iloprost | Indirectly (prostacyclin analog) | Promote vasodilation, enhance oxygen supply | PAH | 2002/1995/2004 |
Selexipag | Indirectly (prostacyclin receptor agonist) | Promote vasodilation, enhance oxygen supply | PAH | 2015 |
Bosentan/Ambrisentan/Macitentan | Indirectly (endothelin receptor antagonist) | Lowers vasoconstriction and pulmonary resistance | PAH | 2001/2007/2013 |
Ivabradine | Indirectly (HCN channel blocker) | Lowering heart rate and enhancing myocardial oxygen utilization | Chronic stable angina | 2015 |
Ranibizumab | Indirectly (VEGF) | Anti-VEGF monoclonal antibody fragment | Retinal vascular disorders | 2006 |
