<P> This generation consists of two groups of compounds, either peptide analogues of the prosegment of renin or peptide analogues of the amino - terminal part of the substrate angiotensinogen . The drugs in the latter group seemed to be effective in inhibiting renin activity and lowering blood pressure in both animals and humans . Unfortunately, they had to be given parenterally because of poor bioavailability . They also turned out to have short durations of action, low potencies and their ability to lower blood pressure was inadequate . None of these drugs completed clinical investigations . </P> <P> Compounds in this generation were more potent, more stable and had longer durations of action . One of these, CGP2928, a peptidomimetic compound, was the first renin inhibitor proven effective when taken orally . Tested on marmosets, it was only active at high doses . Development of new drugs in the second generation continued to improve pharmacokinetic properties . Remikiren, enalkiren and zankiren were then discovered . These were peptidomimetic inhibitors with improved structures that made them more specific, potent and stable . Unfortunately, clinical development was terminated because the drugs had poor oral bioavailability (poorly absorbed and rapidly metabolized) and lowering blood pressure activity still remained low . </P> <P> Aliskiren, an orally active non-peptide renin inhibitor, was the first drug in its class on the market . It is used to treat hypertension as monotherapy or in combination with other antihypertensive agents . The key to the discovery of aliskiren was crystallography and molecular modeling techniques . Now, a solution has been found to the problem that impeded the development of the renin inhibitors of the previous generations . Non-peptide substances were known to be able to solve the problems of poor pharmacokinetic properties and low specificity . This led to the design of small molecules, non-peptide inhibitors, which were very potent and specific of human renin . </P> <P> However, caused by their chemical structure even third - generation renin inhibitors are difficult to resorb by the human body and their oral bioavailability is often below 2% . </P>

Rate limiting step in the production of angiotensin ii