Arete Therapeutics Inc. added $35 million to its Series A financing round, bringing to $51 million the total the company has raised for its new class of drugs targeting hypertension and other conditions.

The Hayward, Calif., company was founded on the use of soluble epoxide hydrolase (s-EH) as an enzyme target for treatment of hypertension and inflammation. S-EH plays a role in a new, third pathway of arachidonic acid metabolism - epoxygenases; the other two, well-validated pathways are cyclooxygenases and lipoxygenases.

Small-molecule s-EH inhibitors under development were described as "hypertension-plus" by Dinesh Patel, president and CEO of Arete. He said the compound appears to have the antihypertensive capabilities of existing agents that effectively lower blood pressure. But the "plus" part comes from the additional potential benefits of protecting against vascular inflammation and protecting organs such as the heart and kidney, he said.

"With these three properties combined, one truly begins to appreciate that this is a unique, first-in-class drug," Patel told BioWorld Today.

The lead drug candidate at Arete is AR9281, which is expected to enter Phase I trials by the end of the year.

Arete Chairman James Topper, general partner at Frazier Healthcare Ventures, said the company also plans to continue work on its "robust backup and second-generation drugs. You have to be smart when developing small-molecule drugs against a new target. We want to have a stable of molecules behind that," which would give the company developmental flexibility.

Frazier Healthcare was among the founding institutional investors of Arete, through the first, $16 million Series A tranche in February 2005. Other founding investors were Alta Partners, Three Arch Partners and Burrill & Co. All four participated in the $35 million extension to the round, which was led by Frazier and Alta. Altitude Life Science Ventures also participated in the extension.

The company actually was founded in 2003 as a virtual company based on work by Bruce Hammock, a professor at the University of California at Davis. Hammock, an entomologist, validated s-EH as a hypertension target over two decades of work that began with studying insects and toxicology. The research was described in a paper in the Dec. 5, 2006, issue of the Proceedings of the National Academy of Sciences. (See BioWorld Today, Dec. 4, 2006.)

"When we first put the syndicate together to finance the company, we wanted - if the company was going well and living up to our expectations - a group that could write checks all the way to the end," Topper told BioWorld Today. By "the end," Topper meant at least through clinical proof of concept in Phase II studies, at which time the plan would be to partner the product through a co-development deal or acquisition, due to the large market size the new class of drugs addresses.

"I don't think we envision Arete as a stand-alone company that would commercialize these products," Topper said. "We have the potential to make enough progress in these programs with this financing that we would see those scenarios playing out over the next two and a half years. This potentially is the last private money to go into this company."

Arete does have an advantage in targeting hypertension, since the lowering of blood pressure is a well-defined and easily measurable endpoint.

The compounds, in addition to cardiovascular benefits, have shown ancillary properties preclinically that could have applicability in inflammatory and metabolic conditions, with metabolic syndrome being one potential additional indication.

"We have found a wonderful molecule, AR9281, and our target has so many nice attributes," Patel said.

The previously studied pathways of arachidonic acid metabolism, cyclooxygenases and lipoxygenases, have been targeted by a number of companies and drugs. Cyclooxygenases, which makes prostaglandins out of arachidonic acid, is targeted by COX-2 inhibitors such as Pfizer Inc.'s Celebrex, as well as by aspirin and non-steroidal anti-inflammatory drugs. Lipoxygenases, which turn arachidonic acid into leukotrienes, are inhibited by products such as Merck and Co. Inc.'s Singulair, which is used to treat allergies and asthma.

"The arachidonic acid pathway has been a great source for the pharmaceutical industry," Patel said. "There's a lot familiarity with that part of the pathway. On the other hand, this is the first instance where somebody is connecting intervention of this pathway to hypertension." He said the company's intellectual property position is solid in terms of coverage of s-EH inhibition for hypertension and inflammation.

In epoxygenases, arachidonic acid is turned into expoxylipids, or EETs, which are broken down by soluble epoxide hydrolase. EETs play an important role in the regulation of arterial pressure during angiotensin II-dependent hypertension, Arete said. It has shown in human tissues and animal models that s-EH inhibitors elevate EET levels, thus lowering blood pressure and preventing or reducing various inflammatory responses.

Arete, which began its transition from a virtual company early in 2006, has 16 full-time employees. It relies on outsourcing arrangements and consultants in many areas of the business.