Antihypertensive drug research and development presents three major trends

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Poor compliance is one of the main problems to be solved in antihypertensive treatment.

The ideal antihypertensive drugs should have the following characteristics: effectively reduce blood pressure, do not produce drug resistance; less adverse reactions, no serious adverse reactions, do not affect the quality of life of patients; do not increase or even improve the risk of cardiovascular disease; can reverse the damage of target organs; it is convenient to take, it is best to take once a day to control blood pressure for 24 hours; the price is cheap.

After decades of development, antihypertensive drugs have evolved from early thiazide diuretics, β-blockers, calcium antagonists and angiotensin-converting enzyme inhibitors (plutons) to angiotensin receptor blockers (sartans). Sartan antihypertensive drugs overcome the possible adverse reactions of the antihypertensive drugs, and their effects are more specific. They are currently a new generation of highly competitive antihypertensive drugs.

Because hypertension is often combined with other cardiovascular diseases, the condition is very complex, patients need to take medicine for a long time, and monotherapy is usually difficult to avoid some side effects, and there is a big problem in the compliance of patients.

Based on the current situation and clinical needs of antihypertensive treatment, the current research and development of antihypertensive drugs mainly develops in three directions: new targets, slow and controlled release technology, and fixed compound preparations.

new target of action

Renin Inhibitors As an initial step in the RAAS system (renin-angiotensin-aldosterone system), renin blocks the pathological effects of the RAAS system by directly inhibiting its activity. The representative variety of renin inhibitor is aliskiren, which is a non-peptide renin inhibitor, developed by Novartis and approved by FDA in 2007. In 2010, aliskiren amlodipine hydrochlorothiazide compound preparation was approved for marketing in the United States. In 2011, worldwide sales of aliskiren amounted to $0.557 billion billion.

Endothelin a receptor (ETAR) antagonist endothelin has potential damage to the heart, kidney and vascular system, endothelin a receptor blocker is expected to become a new drug for the treatment of hypertension. The Representative Variety Darusentan was initially developed jointly by Abbott and Sanofi and later transferred to Gilead. According to the results of clinical trials in 2012, compared with placebo, Darusentan can reduce the systolic and diastolic blood pressure of patients, and does not cause the patient to increase the heart rate when the patient is at rest. However, in a subsequent long-term clinical study, compared with placebo, it was found that the patient's sitting systolic blood pressure did not significantly decrease, so the drug has now terminated its research and development in the field of blood pressure reduction.

Nitric Oxide Donor Nitric Oxide is a potent vasodilator, but its use in the treatment of hypertension is limited due to its short duration of action, poor tachyphylaxis and adverse effects such as headache. The currently developed direct nitric oxide releasing agent, nitrosobalamin, is still in preclinical studies.

Other new antihypertensive drugs include ACE2 activator, aminopeptidase A inhibitor QGC001, etc.

controlled release technique

In order to overcome the short half-life of some antihypertensive drugs and the need to take them multiple times, many companies have developed slow-release antihypertensive drugs.

After felodipine is made into a sustained-release preparation, the number of times the patient takes the drug per day is reduced. Felodipine sustained-release agent quickly occupied the market after listing, sales reached $0.452 billion in 1999, and quickly opened up in the Chinese market. Germany Bayer production of nifedipine sustained-release tablets, in the international and domestic markets have a certain share.

fixed compound preparation

In view of the problems of existing single drugs and the challenges of developing antihypertensive drugs with new mechanisms of action, fixed compound preparations have emerged. The fixed compound preparation has many advantages: the synergistic effect of several drugs can improve the antihypertensive effect; reduce the single dose of each drug, reduce its side effects, or make some side effects offset each other, and the patient's blood pressure drops more smoothly. At the same time, compared with the use of multiple single drugs together, fixed combination preparation helps to increase patient compliance.

Over the past 15 years, many fixed-dose combination drugs consisting of two or more drugs have been approved for marketing around the world. The antihypertensive compound preparations currently in the late stage of research and development are shown in the table.

As can be seen from the table, most of the compound antihypertensive drugs in phase III clinical trials are two-drug or three-drug compound drugs containing one ARB, such as ARB CCB, ARB diuretics, ARB statins, and ARB CCB statins. Amlodipine is one of the preferred drugs in all the above two-drug or three-drug combination products.

The fixed-dose combination treatment plan is also more acceptable to patients, because it reduces the chance of hospitalization, helps to save medical expenses, and also provides a new research and development opportunity for pharmaceutical companies. However, due to the extremely high safety requirements of cardiovascular drugs and the large number of projects required for clinical trials, the development of new antihypertensive drugs has a relatively long research and development cycle, high cost and high risk, which requires pharmaceutical companies to do a good job in preliminary research and project establishment.