Renin inhibitors make progress
orally-active renin inhibitors, a class which have yet to be
commercialised despite two decades of research.
Swiss pharm company Speedel has developed a new series of renin inhibitors (SPP600) that have demonstrated potent activity and oral bioavailability in animal models of hypertension and renal disease.
Renin inhibitors have been pursued as potential new cardiovascular medications since the early-1980s, but to date no drug acting by this mechanism has reached the market. Indeed, some consider that renin inhibition has been the "holy grail" of research into antihypertensive therapies, but technical obstacles have hampered the development of clinical candidates.
Renin is a enzyme in the formation of the neuropeptide angiotensin II, which controls vascular tone, fluid volume and sodium excretion. The renin-angiotensin system has already been established as a target of drug therapy, e.g. when angiotensin converting enzyme (ACE) inhibitors are used to prevent the formation of angiotensin II and lower blood pressure in hypertensive patients or the effects of angiotensin II are blocked using receptor-blocking agents.
The hope is that inhibition of renin levels with highly specific compounds will provide a selective therapy for hypertension, congestive heart failure and associated degenerative disorders linked to angiotensin II. Renin inhibitors also may prove to be more selective than ACE inhibitors for this purpose, for example, because the latter compounds cleave other peptides.
Testing in a rat model that expresses the human genes for renin and angiotensinogen has shown that the new series of renin inhibitors are both potent and orally effective, not only in reducing blood pressure but also in protecting the kidneys.
"These results confirm our molecular modelling and in vitro testing predictions," said Peter Herold, Speedel's director of chemistry.
The development of the SPP600 series is a milestone for Speedel Experimenta, which started up operations 12 months ago. This company was set up to provide an early-stage research function for Speedel, which specialises in licensing later-stage compounds and taking them through clinical trials with a view to re-licensing them to partners.
Speedel already has one renin inhibitor, aliskiren, which was licensed to Novartis after a successful technical and clinical program culminating with a complete Phase II trial dossier.
The new class of compounds is competitive in its profile to valsartan, one of the most successful angiotensin receptor blockers on the market for the treatment of hypertension and renal disease, said Chris Jensen, Speedel's director of pharmacology. "Further testing is ongoing with the goal of selecting a compound for testing in man in 2004," he added.
Speedel is also researching another series of rennin inhibitors (SPP500) licensed from Roche and has an ongoing research collaboration with Locus Pharmaceuticals to generate novel lead compounds in the class.