Novartis’(www.novartis.com) Aliskiren is the first new type of medicine in the management of hypertension, notes N. Claude Cohen, president and CEO of Synergix (www.synergix.com). “Pharmaceutical companies have been working for more than 20 years on this new therapy; it is an area of extreme importance because 50 percent of people affected by hypertension are not adequately controlled with current medication,” says Cohen. “Currently available drugs can help, but there are side effects and complications.”
Cohen has researched this area since the late 1980s. “Back in the early days, peptide molecules were thought to be the mode of delivery,” notes Cohen. “And that was a mistake, since peptides are rapidly metabolized. However, peptides do bind to proteins, so we had to develop a nonpeptide that mimics all the properties of the peptide.”
For this purpose, a homology model of the enzyme was used to characterize the binding mode of a peptide compound, CGP38560, in complex with a model of renin. “We didn’t have an experimental complex between the lead compound and the target, so we developed a model using computer simulation,” says Cohen.
The medical model they used in development of the compound, explains Cohen, is the renin-angiotensin cascade leading to hypertension, which occurs in three levels. “Most drugs in this class can block the cascade at the second and third levels, but the goal was to successfully block the cascade at the first level,” he adds.
Cohen confirms that structure-based drug design played a key role in the process of developing the compound. “It exploits the recognition and discrimination capabilities of the target protein to create favorable interactions in three dimensions with the molecule you conceive.
“To do so, it is necessary to have good knowledge of the 3-D structure of a complex with the protein, which we didn’t. That was where the computer simulations came in,” Cohen says. “And management was surprised when we managed to do it successfully.”
Consequently, four chemically unrelated nonpeptide series were discovered acting as renin inhibitors at the one through three nonmolar level. “We selected one of these leads for further development, and it led to Aliskiren, which was just approved by the FDA in March,” reports Cohen. “The hope is that it will be safe, useful, and efficacious, and that it will work really well with people who don’t currently respond to medication such as the elderly and diabetics.”
“The work of structure-based drug design is to discover the key to the lock,” Cohen concludes. “Disease targets are three dimensional locks, and structure-based drug design is now a mature discipline.”