PDE-5 inhibitor rises to erectile dysfunction challenge
PDE-5 inhibitor for the treatment of cardiovascular diseases,
including endothelial dysfunction and erectile dysfunction.
The study gains additional significance as currently marketed phosphodiesterase-5 (PDE-5) inhibitors have shown limited degrees of efficacy towards cardiovascular diseases primarily due to not having the right combination of potency and duration of action.
SLx-2101 is an oral PDE-5 inhibitor developed to treat endothelial dysfunction, a physiological disability of endothelial cells, the cells that line the inner surface of all blood vessels, arteries and veins, that prevents them from carrying out their normal biochemical functions.
Normal endothelial cells are involved in mediating the processes of coagulation, platelet adhesion, immune function, control of volume and electrolyte content of the intravascular and extravascular spaces. Endothelial dysfunction is believed to be the underlying cause for several major diseases including atherosclerosis, congestive heart failure, hypertension and erectile dysfunction.
The Phase I study is a single centre, randomised, double-blind study designed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects of orally administered SLx-2101 in healthy male subjects.
"We hope to establish a preliminary indication of efficacy in established models of endothelial function. Both peripheral arterial tone and erectile function are being evaluated utilising two non-invasive methods of assessing endothelial function in healthy humans in this study," said Dr William Prince, chief development officer.
"Although the Phase I study has just started, the first PK results look quite promising. Even at a dose of 5mg, we can detect a substantial amount of drug in the blood past 36 hours," added Prince.
Surface Logix's venture into human clinical studies with SLx-2101 represents the company's first drug candidate to enter such an advanced stage. SLx-2101 is one of a series of PDE-5 inhibitors that the company are currently experimenting with and have arisen thanks to its Pharmacomer technology.
"As demonstrated in numerous preclinical animal models, SLx-2101 is a potent and selective compound with rapid cellular and tissue response and an extended duration of action. Our chemistry-based Pharmacomer technology platform permits us to access untapped chemistry space and to bring new functionality to medicinal chemistry," said Dr Paul Sweetnam, chief scientific officer.
"It has allowed us to develop a PDE-5 inhibitor program quite rapidly, from conception to first molecule into the clinic in less than two years," he added.
Surface Logix's Pharmacomer technology is a collection of small molecule functional groups (< 150 MW) that improve the pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of drugs and drug-like molecules.
Pharmacomers are designed using a set of proprietary Assays, Indices and Correlations based on principles from physical chemistry (The Pharmacomer Technology Platform). Using this Platform, scientists can optimise the PK/PD properties of a drug by applying basic principles that govern the interaction of small molecules at the molecular level.
Pharmacomers have been used to minimise non-specific interactions with proteins (e.g., serum albumin, laminin, fibronectin) thereby improving distribution of drugs to desired receptors and enzymes in a specific tissue or organ.
The technology has also been used to improve metabolic stability by minimising breakdown by catabolic enzymes (e.g, cytochrome P450 enzymes and conjugating enzymes).
In addition, it has been used to improve membrane permeability to barrier cells (e.g, CaCO2 and MDCK) and target cells (e.g, neuronal, endothelial and smooth muscle cell).
Since Pfizer's Viagra (sildenafil) was approved in 1998, annual global sales have reached $1.9bn (€1.5bn). The product had the oral ED market to itself until last year, when two rivals entered the market, namely Levitra (vardenafil) from GlaxoSmithKline and Bayer, and Cialis (tadalafil) from Eli Lilly and Icos. Both these drugs have the same mechanism of action as Viagra.
At the European Association for Urology meeting in Vienna, Cialis claimed it had overtaken Levitra in the USA in terms of new prescriptions written (18 per cent versus 15 per cent).
Bayer and GSK commented that by the end of 2003, market share in the US was 10 per cent based on sales of 7m tablets compared to 2m for Cialis. GSK reported that Levitra sales were £37m (€55.4m) in 2003, while Bayer said the drug brought in €144m.
