Captopril structure-based design

The ACE-inhibitor captopril is frequently quoted as the first example of a drug which was obtained from structure-based design. Indeed, in the paper describing the discovery of captopril, Cushman and coworkers emphasize the value of their active site model of ACE in the design of captopril [16], As the 3D structure of ACE was not known by Cushman, the work... 

FIGURE 30.2 The first marketed drugs derived from structure-based design, (a) captopril (Capoten ), (b) dorzolamide (Trusopt ), (c) zanamivir (Relenza ), and (d) oseltamivir (Tamiflu ). 

In a discovery project that is reminiscent of the discovery of captopril, scientists at Takeda created a hypothetical structure for the active site of acetylcholinesterase, based on SAR from previous biochemical and medicinal chemical work (141). The model consisted of (in addition to the serine protease-like catalytic machinery) an anionic binding site separating two discrete hydrophobic binding sites. This model was then used to design inhibitors of the enzyme (reviewed i n ref. 142). One set of analogs examined were based on the N-((o-phthalimidylalkyl)-iV-(a)-phenylalkyl)-amine (scaffold 66). An iterative process of testing. 

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