Pharmacopeia tout 2-for-1 cardiovascular drug

By Mike Nagle

- Last updated on GMT

Scientists at Pharmacopeia have stitched together the active parts
of two molecules to form a single drug, which it claims could treat
several cardiovascular diseases more effectively, including kidney
disease caused by diabetes.

The US company believe PS433540, which recently began a Phase I clinical trial, is the first and only molecule of its kind, for which the company has coined the term Dual Acting Receptor Antagonist (DARA). The unique molecule combines the receptor blocking effects of two vasodilating drugs that target either angiotensin II (AII) or endothelin 1 (ET1) receptors.

By blocking both at once, Pharmacopeia hopes its drug will prove superior to either molecule alone at treating hypertension, congestive heart failure and diabetic kidney disease (nephropathy). Diabetic nephropathy represents a large, growing unmet medical need with a high mortality rate, affecting an estimated 8m diabetics in the US, Europe and Japan.

The idea of combining the effects of multiple drugs into a single molecule is not new. However, other pharma companies that have tried to achieve it have met with limited success.

"It is hard to get a balance of potency and difficult to get the right metabolic properties. For example, metabolites could retain activity but only for one of the targets,"​ Dr Leslie Browne, CEO of Pharmacopeia, explained to

"Preclinical studies have shown that PS433540 has a nice balance of potency at both targets and its metabolites lose that activity, at both receptors. PS433540 is a unique compound that could have the activities of two drug classes,"​ he added.

The molecule was designed after scientists at Pharmacopeia noticed that two drug molecules shared a common structural feature. Bristol-Myers Squibb and Sanofi-aventis jointly market blockbuster drug Avapro (irbesartan), which is an AII receptor blocker with combined sales last year of $3.4bn (€2.6bn). Bristol-Myers Squibb was also developing an endothelin 1 receptor blocker called BMS-193884, although it no longer appears on the firm's pipeline listing.

Pharmacopeia used a common feature of both of these drugs as a base on which to combine their active parts and form PS433540. The first subjects have already been dosed in the 'first-in-man' trials and the pharma firm hopes to report the results in the middle of this year.

Dr Leslie also said that the company would soon start an angiotensin challenge study with the results due at the same time. In the study, a healthy volunteer has their blood pressure temporarily raised artificially with and without an investigational drug present in order to measure the drugs efficacy.

Endothelin 1 has two receptors, A and B. Blocking endothelin binding to receptor A prevents blood vessels from constricting whereas preventing binding at receptor B has a negative effect on patients because, for example, it reduces the production of the vasodilator molecule, nitric oxide.

Tracleer (bosentan) is an example of a drug that binds to both receptors. It is marketed by Actelion Pharmaceuticals as a treatment for pulmonary arterial hypertension. The DARA compound, however, selectively inhibits endothelin A with a ration of 10,000 to 1, according to Dr Leslie.

If approved, Tracleer would be one of the main rivals of PS433540. However, other ET1 receptor blockers are also in development, such as Gilead's ambrisentan and darusentan - currently the subjects of a New Drug Application (NDA) and Phase IIb clinical trials respectively. Myogen originally developed both drugs before they were acquired by Gilead in November 2006.

Encysive Pharmaceuticals has developed a selective endothelin receptor blocker, which is currently approved for use in Europe and in Phase III clinical trials for use in the US. Thelin (sitaxsentan) is 6000 times more likely to bind to endothelin receptor A than B, according to the US based company.

Other than Avapro, other angiotensin II receptor blockers currently approved are Diovan (valsartan) from Novartis and Cozaar (losartan) from Merck & Co.

Meanwhile, Speedel pharmaceuticals has recently placed the development of SPP301, an endothelin receptor A blocker, on hold amid safety concerns. In December 2006, a Phase III trial testing the drug as a treatment for diabetic neuropathy was halted.

Related topics Preclinical Research

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