Renin inhibitors are a new class of compounds under development for the treatment of hypertension, chronic renal disease and congestive heart failure. More than 50 per cent of patients with high blood pressure are not adequately controlled with current drugs adding impetus to additional therapeutic options. Global antihypertensive drugs sales are forecasted by Datamonitor to grow from $40 billion (€30.7 billion) in 2003 to $50 billion (€38.3 billion) by 2009.
Speedel has used rational drug design, preclinical modelling and human microdosing to obtain early ADME information on its two renin inhibitor candidates, SPP630 and SPP635, allowing researchers to 'screen-in' the most promising candidates for clinical development.
Such selections are usually made in the absence of human data, but Speedel's adoption of microdosing has allowed the company to reach this stage in less than 9 months from first synthesis of a compound to human testing.
SPP630 and SPP635, compounds with low nanomolar potency, have now been successfully tested in microdosing studies with human volunteers and in preclinical studies with transgenic rats that express the human genes for renin and angiotensinogen.
Microdosing relies on the ultrasensitivity of Accelerator Mass Spectrometry (AMS). Using AMS it is possible to conduct a full human metabolism study after administration of as little as 0.1 milligram of drug substance, measuring drug concentrations in biological fluids up to 1000 times less than the levels one observed in Phase I clinical study.
"Our approach with the use of human microdosing has allowed us to fast-track these compounds to a stage where we expect to select the best candidate(s) to continue classical Phase I studies in Q3 2005," commented Dr Alice Huxley, CEO of Speedel.
Renin inhibitors have become the latest potential therapeutic agents for hypertension in a market that has become increasingly overcrowded. Renin is an enzyme produced in the kidneys in response to reduced renal perfusion. Through a cascade of biological events, renin acts to bring about sodium retention, an increase in blood pressure, and restoration of renal perfusion, which shuts off the signal for renin release.
For hypertensive individuals, renin inhibitors are currently being investigated as a therapy that may provide benefits over current therapies to reduce blood pressure, decrease salt retention and may protect end organs such as the kidney, heart and brain.
Inhibition of renin articulated as Plasma Renin Activity (PRA), is important in end-organ protection (e.g. heart and kidney). PRA is an independent and surrogate marker for several cardio-renal diseases, such as myocardial infarction and chronic renal disease. Only Renin Inhibitors lower PRA efficiently, whereas current antihypertensive therapies increase PRA levels.
The studies have shown both compounds demonstrated bioavailability in humans of up to 30 per cent and in rats of 70-90 per cent. This data represents improvement over figures obtained from any previous renin inhibitor.
In addition, results revealed larger tissue distribution than previous renin inhibitors, indicating potential for end-organ protection. Blood pressure was reduced in transgenic rats over 24 hours and there was noticeable slow down in the renal damage progression after oral treatment.
Other results showed a half-life of more than 30 hours in man, making them suitable for once-a-day dosing.
Speedel commented that both SPP630 and SPP635 would be evaluated in toxicology studies before a decision was made about which compound(s) would continue in Phase I studies with single and multiple ascending doses.
Hypertension is a common disorder in which blood pressure is abnormally high, placing undue stress on the heart, blood vessels and other organs such as the kidney and the brain. Blood pressure is determined in two phases as the heart contracts and relaxes. Systolic blood pressure represents the force that blood exerts on the walls of arteries as the heart contracts to pump out blood. Diastolic blood pressure represents the force as the heart relaxes to allow the blood to flow into the heart.
Due to its wide prevalence and impact on cardiovascular health, hypertension is a major cause of disease and death in Europe and North America. More than one in three Europeans and North Americans over the age of 35 suffers from hypertension. The vast majority of patients who undergo hypertension treatment, the causes of high blood pressure are unknown.