Archive for the ‘renin’ Category

Finally, a renin inhibitor makes it to market

March 15, 2007

Very recently approved…Novartis’ Tekturna® (aliskiren) is the first new treatment for hypertension to reach the market in over 10 years. However, the story on how this drug made it market goes back even further. An interesting review was published last year in The Lancet, which believe it or not actually contains chemical structures.

As an indication of how old (or young depending on your perspective) I am, renin was a very “hot” target when I was interviewing for my first job a number of years ago. It seemed like every company I visited had a high profile renin program. Back then renin was not just a target, rather it representative a whole paradigm for discovering drugs, namely the combination of “peptidomimetics” and computer aided drug design. The idea was to exploit peptides as leads which and then be convert them into bona fide drug like compounds by tweaking the backbone. Renin was a prime example of this approach.

Of course, renin had been contemplated as a target for treating hypertension since the 1950’s (Skeggs et al. J. Experimental Medicine 1957, 106, 439) but it took some time to figure out how to develop an oral drug.

The aspartyl protease, renin, lies at the beginning of the renin-angiotension system (RAS) that ultimately, results in the synthesis of the peptide angiotensin II (AII). AII acts at the kidneys to increase Na+resorption, vasoconstriction and water retention, resulting in increased blood pressure. As shown below, cleavage of angiontensinogen to angiotensin I (AI) is the first step in the cascade, after which angiotensin converting enzyme (ACE) converts AI into AII via a second proteolytic reaction.


Over the years a number of agents have been developed that inhibit various steps of the process. For example, b-blockers hamper the release of renin from the kidneys, ACE-inhibitors prevent the conversion of AII to AI, while AII-antagonists block the action of AII at the kidneys. While these drugs have found wide use in the treatment of hypertension, each has its own set of issues.

In addition to preventing the cleavage of AI to AII, ACE-inhibitors also block the proteolytic inactivation of bradykinin and substance P, leading to two common side-effects…a dry cough and in some cases angioedema while AII-antagonists show limited receptor subtype activity.  Because renin is upstream form these events, a therapeutic which targeted this enzyme should be free form these side effects and limitations.

From the beginning, the primary problem in this area was not the lack of leads but the compounds that were active against the enzyme were large, peptide like compounds…very “non-drug” like according to the most lenient standards. This was no accident since the majority of these compounds were designed using the peptide substrate as a starting point. Examples of 1st generation compounds are, shown below. CGP-29287 (the first compound to demonstrate oral activity), A72517 (zankiren), A64662 (enalkiren), Ro 42-5892 (remikiren), U-71038 (ditekiren)…etc.

Novartis (Ciba-Giegy at the time), discovered aliskiren in the early 90’s but licensed it out to Speedel since it it appeared to expensive to make. Speedel was able to develop a cost-effective method for producing the compound and examined the compound all the way through to phase III, at which point Novartis exercised its “call back” option and filed the compound for approval.

Interestingly enough, Roche appears to be pursuing a similar pathway, in that they also have handed over their renin program to Speedel. The exact structure(s) have not been released but one of Roche’s advanced compounds had been remikiren.

Evidently, for renin, patience and perserverence has finally paid off. It will be interesting to see if other companies decide to jump in this area as well.