Medical Network News on August 6th Poor compliance is one of the main problems to be solved in current antihypertensive treatment.

Ideal anti-hypertensive drugs should have the following characteristics: effectively lower blood pressure without drug resistance; few adverse reactions, no serious adverse reactions, and no impact on the patient’s quality of life; and do not increase or even improve the risk of cardiovascular disease ; It can reverse the damage of the target organ; it is convenient to take, it is best to take it 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 (pristines) to vascular tension. Receptor blockers (sartans). Sartan anti-hypertensive drugs overcome the possible adverse reactions of pristine anti-hypertensive drugs, and their effects are more specific. They are currently a new generation of highly competitive anti-hypertensive drugs.

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

Based on the current status and clinical needs of antihypertensive therapy, the current research and development of antihypertensive drugs are mainly developed in three directions: new targets, slow and controlled release technologies, and fixed compound preparations.

New target

Renin inhibitors Renin, as the initial step of the RAAS system (renin-angiotensin-aldosterone system), can block the pathological effects of the RAAS system by directly inhibiting its activity. The representative variety of renin inhibitors is Aliskiren, which is a non-peptide renin inhibitor developed by Novartis and was approved by the US FDA for marketing in 2007. In 2010, aliskiren, amlodipine, and hydrochlorothiazide compound preparations were approved for marketing in the United States. In 2011, Aliskiren's global sales reached 557 million U.S. dollars.

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 type of drug for the treatment of hypertension. The representative variety Darusentan was originally jointly developed by Abbott and Sanofi, and then transferred to Gilead. According to the results of clinical trials in 2012, compared with placebo, Darusentan can reduce the patient's systolic and diastolic blood pressure without causing an increase in the patient's heart rate at rest. However, in a subsequent long-term clinical study, compared with placebo, it was found that the patient's systolic blood pressure did not decrease significantly in the sitting position, so the drug has now terminated its research and development in the field of blood pressure.

Nitric Oxide Donor Nitric oxide is a potent vasodilator, but its use in the treatment of hypertension is limited due to its short acting time, poor rapid tolerability, and headaches. The currently developed direct nitric oxide release agent-nitrosocobalt ammonium is still in pre-clinical research.

Other new antihypertensive drugs under development include ACE2 activator, aminopeptidase A inhibitor QGC001 and so on.

Slow and Controlled Release Technology

In order to overcome the shortcomings of some antihypertensive drugs that have short half-lives and need to be taken multiple times, many companies have developed slow- and controlled-release antihypertensive drugs. For example, after felodipine is made into a sustained-release preparation, the number of medications taken by patients per day is reduced. Felodipine sustained-release agent quickly occupied the market after it went on the market. In 1999, its sales reached 452 million U.S. dollars and quickly opened up in the Chinese market. The sustained-release tablets of nifedipine produced by German Bayer have a certain share in both the international and domestic markets.

Fixed compound preparation

In view of the existing problems of single drugs and the challenges of developing antihypertensive drugs with new mechanisms of action, fixed compound preparations have emerged. Fixed compound preparations have 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 multiple single drugs used together, fixed compound preparations help increase patient compliance.

In the past 15 years, many fixed-dose compound drugs consisting of two or more drugs have been approved for marketing worldwide. 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, ARB CCB statins. Among all the above-mentioned two-drug or three-drug compound products, amlodipine is one of the priority drugs.

The fixed-dose combination treatment plan is also easier for patients to accept, because it reduces the probability of patients being hospitalized, is conducive to saving medical costs, and also provides a new R&D opportunity for pharmaceutical companies. However, due to the extremely high safety requirements of cardiovascular drugs, and the number of projects required for clinical trials, the development of new antihypertensive drugs requires a relatively long R&D cycle, high cost and high risk, which requires pharmaceutical companies to Do a good job of preliminary investigation and project approval.