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A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.
Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.
Tumor necrosis factor is an adipokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.
Alpha-1 blockers constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. Alpha-1 adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.
Anagrelide is a drug used for the treatment of essential thrombocytosis, or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.
Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.
Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.
Amlexanox is an anti-inflammatory antiallergic immunomodulator used to treat recurrent aphthous ulcers, and several inflammatory conditions. This drug has been discontinued in the U.S.
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.
Etazolate (SQ-20,009, EHT-0202) is an anxiolytic drug which is a pyrazolopyridine derivative and has unique pharmacological properties. It acts as a positive allosteric modulator of the GABAA receptor at the barbiturate binding site, as an adenosine antagonist of the A1 and A2 subtypes, and as a phosphodiesterase inhibitor selective for the PDE4 isoform. It is currently in clinical trials for the treatment of Alzheimer's disease.
Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.
Pirfenidone, sold under the brand name Pirespa among others, is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II.
Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically related PDE5 inhibitors, such as sildenafil (Viagra), which successfully reached the market. It is a phosphodiesterase inhibitor, selective for the subtypes PDE5, PDE6, PDE9 and PDE11. IC50 values are 0.76, 0.15, 29.0, and 12.0 μM, respectively.
O-1602 is a synthetic compound most closely related to abnormal cannabidiol, and more distantly related in structure to cannabinoid drugs such as THC. O-1602 does not bind to the classical cannabinoid receptors CB1 or CB2 with any significant affinity, but instead is an agonist at several other receptors which appear to be related to the cannabinoid receptors, particularly GPR18 and GPR55. These previously orphan receptors have been found to be targets for a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the non-CB1, non-CB2 mediated effects that have become evident in the course of cannabinoid research. O-1602 produces some effects shared with classical cannabinoid compounds such as analgesic and antiinflammatory effects and appetite stimulation, but it does not produce sedation or psychoactive effects, and has several actions in the gut and brain that are not shared with typical cannabinoid agonists.
Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.
SGLT2 inhibitors are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium/glucose cotransporter 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.
HL156A is a derivative of metformin and a potent oxidative phosphorylation inhibitor and AMP-activated protein kinase activating biguanide. Certain types of cancer cells requires oxidative phosphorylation to survive. By targeting it, HL156A might help in improving anticancer therapy. It is more potent than acadesine or metformin at activating AMP-activated protein kinase. It is synthesized by Hanall Biopharma.
References
- 1 2 3 4 Zheng, Lei; Zhou, Zhong-Zhen (November 2023). "An overview of phosphodiesterase 9 inhibitors: Insights from skeletal structure, pharmacophores, and therapeutic potential". European Journal of Medicinal Chemistry. 259: 115682. doi:10.1016/j.ejmech.2023.115682.
- ↑ Mishra, Sumita; Sadagopan, Nandhini; Dunkerly-Eyring, Brittany; Rodriguez, Susana; Sarver, Dylan C.; Ceddia, Ryan P.; Murphy, Sean A.; Knutsdottir, Hildur; Jani, Vivek P.; Ashok, Deepthi; Oeing, Christian U.; O’Rourke, Brian; Gangoiti, Jon A.; Sears, Dorothy D.; Wong, G. William; Collins, Sheila; Kass, David A. (1 November 2021). "Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice". The Journal of Clinical Investigation. 131 (21). doi: 10.1172/JCI148798 . ISSN 0021-9738. PMC 8553561 .
- ↑ Wu, Yinuo; Wang, Quan; Jiang, Mei-Yan; Huang, Yi-You; Zhu, Ziran; Han, Chuan; Tian, Yi-Jing; Zhang, Bei; Luo, Hai-Bin (8 July 2021). "Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis". Journal of Medicinal Chemistry. 64 (13): 9537–9549. doi:10.1021/acs.jmedchem.1c00862. ISSN 0022-2623.
- ↑ Richards, Daniel A.; Aronovitz, Mark J.; Liu, Peiwen; Martin, Gregory L.; Tam, Kelly; Pande, Suchita; Karas, Richard H.; Bloomfield, Daniel M.; Mendelsohn, Michael E.; Blanton, Robert M. (January 2021). "CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload–Induced Heart Failure". Circulation: Heart Failure. 14 (1). doi: 10.1161/CIRCHEARTFAILURE.120.007300 . ISSN 1941-3289. PMC 8451972 .
- ↑ Ribaudo, Giovanni; Landucci, Elisa; Giannangeli, Matteo; Mazzantini, Costanza; Maccarinelli, Giuseppina; Mastinu, Andrea; Bonini, Sara Anna; Memo, Maurizio; Pellegrini‐Giampietro, Domenico E.; Gianoncelli, Alessandra (2023). "Virtual screening and in vitro experiments highlight cannabidiol as a drug‐like phosphodiesterase 9 inhibitor". European Journal of Neuroscience. 57 (12): 1954–1965. doi:10.1111/ejn.15869. hdl: 2158/1322316 .
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