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Page 598<br />

as hydrogen-bonding to the backbone of the inhibitor that exists in β-sheet type extended conformation.<br />

<strong>Structure</strong>-<strong>based</strong> design strategies of renin inhibitors have focused on systematic transformation of its<br />

substrate (angiotensinogen). Noteworthy examples which illustrate topographical designed include<br />

inhibitors 96 [152], 97 [153], 98 [154], and 99 [155], of which the latter macrocyclic inhibitor is quite<br />

novel in terms of having two D-aromatic amino acids and lacking a “transition state” bioisostere<br />

replacement at the P 1-P 1' site.<br />

In contrast to renin, the discovery of HIV protease inhibitors provides a high degree of synchronization<br />

of x-ray crystallography studies with iterative structure-<strong>based</strong> drug design efforts as well as the<br />

identification of nonpeptide ligands from mass screening (e.g., coumarins and pyrones) or 3D<br />

computational searching (e.g., haloperidol) to advance what has become a milestone achievement in<br />

rational drug design [113]; and for reviews on HIV protease see Reference 156 and the first chapter of<br />

this book). Representative of the scope of the many contributions to the discovery of both<br />

peptidomimetic and nonpeptide inhibitors of HIV protease (Figure 23) are the de novo designed C 2symmetric<br />

http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_598.html (1 of 2) [4/9/2004 1:27:18 AM]

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