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Phosphodiesterase inhibitor

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phosphodiesterase inhibitor It is a drug used to inhibit the activity of phosphodiesterase. Selective phosphodiesterase 3, 4 and 5 inhibitors Heart failure 、 asthma 、 Impotence And other diseases. Make by suppression cAMP The cleaved phosphodiesterase F - Ⅲ inhibits the cleavage of cAMP and increases the concentration of cAMP in cells calcium ion Inward flow , generated Positive muscle strength In addition to positive inotropic effect, phosphodiesterase inhibitor also increases blood vessel smooth muscle cell The content of cAMP has the effect of vasodilation.^[1] 。

Chinese name: Phosphodiesterase inhibitor
Foreign name: Phosphodiesterase inhibitor

Abbreviation: PDEs
Type: Drugs inhibiting phosphodiesterase activity

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seven 7. PDE7 and its inhibitor

1. Analysis of action mechanism

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Cyclic adenosine phosphate (c AMP) and Cyclic guanosine phosphate (c GMP) are two important intracellular Second Messenger It participates in various metabolic activities of the body through special receptors, and its intracellular concentration is mainly regulated by the gland (bird) Glycosidic acid Cyclase Synthesis and phosphodiesterase (P DE s) Hydrolysis Balance between decisions. P DE s can specifically nucleotide As a substrate, it catalyzes the hydrolysis of cGMP and cAMP in cells to generate corresponding inactive 5-nucleotides, thus affecting various metabolic functions of organisms.

2. PDE1 and its inhibitor

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PDE1 is one of the first PDE isozymes discovered, which can hydrolyze cAMP and cGMP. There are three known PDE1 subtypes: PDE1A, PDE1B and PDE1C. PDE1A and PDE1B have strong hydrolysis ability to cGMP, while PDE1C has no significant difference in the hydrolysis ability to cAMP and cGMP. PDE1A is mainly distributed in blood vessels smooth muscle cell Medium, adjustable smooth muscle Nervousness PDE1B is mainly distributed in nervous system Middle, participate in learning and memory Immunomodulation PDE1C is mainly distributed in the brain and smooth muscle cells, which may be involved in the proliferation of vascular smooth muscle cells and central nervous system Signal transmission of. PDE1 mainly plays a role by binding with Ca2+/CaM. After binding, PDE1 contains two Catalytic subunit And two calmodulin Molecular composition, single nucleotide in the second messenger ring phosphoric acid And Ca2+, such as odor molecules and olfactory receptor After binding, it is activated through the olfactory specific channel Gs protein Adenylate cyclase CAMP acts on olfactory specific cyclic nucleotide gated ion channels to increase intracellular Ca 2+concentration, and then activates Ca 2+regulated Chloride ion Channel, forming chloride ion current, thus producing a specific sense of smell. PDE1 can specifically hydrolyze cAMP, reducing the concentration of Ca2+in cells, thus terminating the transmission of olfactory signals.

Up to now, the discovered PDE1 selective inhibitors mainly include Nimodipine 、 Vinpocetine IC86340, IC224, etc. Pattyar et al. believed that vinpocetine had anti-inflammatory effect and could improve endothelium Dysfunction as well as atherosclerosis , and lower Cerebral apoplexy Probability; At the same time, vinpocetine is improving Cognitive dysfunction It also plays a role. At present, the drug has been used in clinical treatment Parkinson's disease Parkinson's disease (PD) and Alzheimer disease, AD ）Etc Neurodegenerative disease 。 It is reported that the application of Ca2+channel Antagonist Nimodipine can significantly reduce aneurysm Subarachnoid hemorrhage Patient's Cerebral vasospasm To improve the brain Local ischemia So as to prevent the rebleeding of the brain and delay the rebleeding of the brain ischemia Occurrence of. Jeon et al. pointed out that IC86340 and vinpocetine can regulate β - chain protein by Signal path To promote the proliferation of vascular smooth muscle cells.

3. PDE2 and its inhibitor

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PDE2 can hydrolyze cAMP and cGMP, and binding PDE2 with cGMP can enhance its ability to hydrolyze cAMP. PDE2 has only one subtype PDE2A, but PDE2A contains three subtypes: PDE2A1, PDE2A2, and PDE2A3 due to different initial codons. PDE2 is expressed in many tissues and cells, such as the central nervous system, platelets, myocardial cells, endothelial cells, etc. PDE2A1 mainly exists in the cell matrix, while PDE2A2 and PDE2A3 exist in cell membrane On. Since PDE2 can further induce hydrolysis of cAMP after combining with cGMP, PDE2 may participate in the regulation of the intersection of cAMP and cGMP signals in vivo. In addition, PDE2 can regulate myocardial contraction, improve cognitive function and long-term memory All aspects play an important role.

At present, PDE2 inhibitors mainly include EHNA, BAY60 - 7750, IC933 and Dipyridamole Etc. It is reported that EHNA can inhibit Malignant melanoma Cells DNA Synthesis, make tumor cell cycle Stay in G2/M. In addition, cells treated with EHNA Cyclin A's mRNA The expression of S phase regulatory protein is reduced Cyclin The increased expression of E mRNA affects the cell cycle of malignant melanoma, which provides a new possibility for clinical treatment of malignant melanoma. It is confirmed by the research that, before adding Exogenous In the case of cytokines, EHNA can inhibit embryonic stem cell neuron Differentiation and spontaneity Differentiation, indicating that EHNA inhibits the differentiation of tissue embryonic stem cells and maintains its Pluripotency It also plays an important role; Dipyridamole has the function of anti platelet aggregation, and is used to treat ischemic cardio cerebrovascular diseases; Domek -  opaci ń ska et al found that BAY-60-7550 can regulate the NO/cGMP signaling pathway, thereby improving the cognitive and long-term memory functions of AD patients and brain aging patients. Compared with PDE1 inhibitors, PDE2 selective inhibitors have a clear mechanism of action, which provides a good treatment for improving learning and cognitive function.

4. PDE3 and its inhibitor

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PDE3 vs. cAMP cGMP All of them have hydrolysis capacity, but the hydrolysis capacity for cAMP is about ten times that for cGMP. PDE3 has two genotypes: PDE3A and PDE3B, which are located on chromosomes 11 and 12 respectively Initial codon PDE3A can be divided into three subtypes: PDE3A1, PDE3A2 and PDE3A3, which are mainly distributed in the heart platelet , vascular smooth muscle and oocyte Medium, with adjustment Myocardial contractility 、 platelet aggregation Vascular smooth muscle contraction, oocyte maturation and renin release. PDE3B has only one subtype PDE3B1, mainly distributed in fat cells 、 Hepatocyte 、 Spermatocyte And pancreas, mainly involved in regulation insulin 、 Insulin like growth factor as well as leptin Of signal transduction , in obesity and diabetes etc. Metabolic disease Plays an important role in. PDE3 selective inhibitors mainly include Cilostazol , Siloramide Milrinone 、 Ammorinone , enoxidone and Cyanoguanidine Zuo Dan et al. Shi Lingyun and others pointed out that amrinone can inhibit the activity of PDE3, increase the concentration of cAMP in myocardial cells, and increase the concentration of Ca2+in cells, so as to give full play to Positive muscle strength effect. At the same time, Amrinone Direct action It has good vasodilation effect on vascular smooth muscle cells, increases myocardial contractility, and reduces pulmonary artery Pressure, recovery Cardiopulmonary function , in chronic pulmonary heart disease merge heart failure It has important value in the treatment. In addition, cilostazol has passed the certification of the U.S. Drug and Food Administration (FDA), and is clinically used for anti platelet aggregation Pulmonary hypertension ( pulmonary hypertension，PAH) 、 Chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD), intermittent claudication and treatment of cerebrovascular diseases. In recent years, the research on the inhibition of PDE activity of traditional Chinese medicine ingredients has gradually increased. Tan Ping and others found that traditional Chinese medicine Ginkgo biloba extract Similar to PDE3 inhibitor, it can Acute cerebral infarction The activity of PDE3 in platelets of patients decreased, which greatly increased the level of intracellular cAMP, effectively inhibited platelet aggregation, and improved Hemorheology And the effect of neurological deficit.

5. PDE4 and its inhibitor

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PDE 4 pairs of cAMP with height Specificity There are four subtypes: PDE4A, PDE4B, PDE4C and PDE4D. Each PDE4 gene has multiple Transcription unit and Promoter , about 20 PDE4s Isoenzyme , widely distributed in various tissues and cells of human body, such as brain, kidney Cardiac myocyte ， endothelial cells and Immune cell Medium. PDE4 participated in promoting monocyte And Macrophage activation 、 Neutrophils Infiltration, blood vessel smooth muscle Proliferation Vasodilation as well as Myocardial contraction And other related physiology Pathological process , Yes central nervous system Function cardiovascular Function, inflammation/ immune system 、 cell adhesion And so on.

At present, the research on PDE4 is mainly focused on immune and inflammation related diseases. Many famous pharmaceutical companies in the world regard PDE4 as chronic inflammation Target of related diseases. PDE4 inhibitor The anti-inflammatory effect can be exerted mainly through the following ways: (1) inhibition of multiple Inflammatory mediators Activity; ( 2) Suppressor cell Upregulation and expression of adhesion factor; (3) Inhibition of blood white blood cell Activation; (4) Induction Apoptosis ; (5) Induce those with inhibitory activity cell factor Generation of (e.g Interleukin-6 ) ; (6) Induction catecholamine Substance like and endogenous hormones Release of. The first generation PDE4 inhibitors mainly include theophylline 、 Roliplan And piramist, etc., and rolipram Nervous system diseases , such as PD depression And anxiety have certain therapeutic value. However, the first generation PDE4 inhibitors are limited in clinical application due to severe side effects such as nausea and vomiting; The second generation PDE4 inhibitors include Roflunst and Sylvester And so on, among which, Roflunst has passed FDA And the European Medicines Agency for COPD Treatment. In addition, Roflukast Inflammatory disease It also has certain therapeutic effects, such as Ulcerative colitis and Crohn's disease 。 The third generation PDE4 inhibitor Apste has been used for Autoimmune disease as Psoriasis The side effects are less and the patients are more tolerant.

6. PDE5 and its inhibitor

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PDE5 can specifically hydrolyze cGMP, and there is only one subtype PDE5A. Due to different initial codons, PDE5A can be divided into PDE5A1, PDE5A2 and PDE5A3. PDE5 is mainly distributed in the lungs, pancreas, brain Corpus cavernosum penis , vascular smooth muscle cells, platelets Skeletal muscle cells And myocardial cells. PDE5 can regulate the contractility of vascular smooth muscle, especially the contractility of penile and pulmonary vascular smooth muscle. PDE5 can also pass NO cGMP signal transmission PDE5 may also play an important role in cGMP signal transmission in the brain.

PDE5 Selective inhibition Agents mainly include Sildenafil , Vardenafi He Danafei 、 Minchuanning And Utinafil. Sildenafil is not just for men erectile dysfunction ( erectile dysfunction， ED ）It can also be used to treat PAH and improve the patient's dyspnea 。 Yanagisawa et al. reported that sildenafil was found to be an important drug for PAH patients First-line medication , can significantly improve the patient's Survival rate And improve it Quality of life 。 Some studies have also proved that patients with PAH take 40 mg of tadalafil every day, Quality of life It has been improved and the deterioration of the disease has been slowed down. In addition, in recent years, researchers have also carried out active research on PDE5 inhibitors in anti-cancer. Tinsley and other studies show that sildenafil may participate in the selective inhibition of sulindac mammary cancer Cell growth and induction cancer cell The process of apoptosis.

7. PDE7 and its inhibitor

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The biological function of PDE7 family is similar to that of PDE4, and it has high selectivity to cAMP. As a new therapeutic target for chronic inflammation, PDE7 family has attracted more and more attention. There are two subtypes of PDE7 family, PDE7A and PDE7B, whose gene sequence homology is as high as 70%. Among them, PDE7A includes three subtypes: PDE7A1, PDE7A2 and PDE7A3. PDE7A is mainly distributed in the brain, spleen, lung, thymus and various lymphocyte In, especially in macrophage And T lymphocytes. PDE7B also has three subtypes: PDE7B1, PDE7B2 and PDE7B3. PDE7B mainly exists in the heart, brain, lung, kidney, liver, testis and Muscle tissue Medium.

At present, BRL-50481 and IC242 as well as PDE7 selective inhibitors based on computer simulation Discovered Quinazoline Class and Thiadiazole class Small molecule Compounds S14 and VP1.15, etc. BRL - 50481 can be lowered Chronic lymphocytic leukemia ( CLL ）The expression of PDE7B protein in CLL cells increases the content of cAMP, thereby inducing CLL cell apoptosis. In addition, BRL 50481 combined with other inhibitors can enhance the effect of other PDE inhibitors, such as BRL 50481 alone acting on CD8+T lymphocytes, monocytes Pulmonary macrophage CD8+T Lymph cell proliferation No obvious changes, monocytes and pulmonary macrophages tumor necrosis factor (TNF - α) production is only reduced by 2% - 11%, but it can significantly enhance the effect of PDE4 inhibitor rolipram on the above three cell line Proliferative inhibition And significantly reduce the production of TNF - α, thereby enhancing its anti-inflammatory effect. Newly discovered S14 and VP1.15 IC50 5 5 and 1 1 μ mol ·L-1, they can increase the concentration of intracellular cAMP by inhibiting the activity of PDE7, play an anti-inflammatory role, and effectively reduce mice because inflammatory reaction Caused by Spinal cord injury Of Secondary damage 。

Due to the lack of in-depth research on other PDE family members, PDE6, 8, 9 and 11, there are few reports, so no in-depth explanation will be made here. PDE6 exists in retina In rod cells, cGMP is specifically hydrolyzed, which may be used in treatment Hereditary color blindness 、 Retinitis pigmentosa And other diseases; PDE8 can specifically hydrolyze cAMP, which may be involved in regulation Ventricular myocyte Excitation contraction coupling Isophysiological activity; PDE9 can specifically hydrolyze cGMP, which can Improve memory And cognitive function; In recent years, it has been reported that PDE10 may participate in the process of pulmonary artery remodeling, which can be a potential target for PAH treatment; Lib é and others reported that PDE11A may be associated with testicles and adrenal tumors There is a certain correlation between PDE11 and PDE11.

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