Captopril design/discovery

Figure 10.8. Active site models for car-boxypeptidase A (top) and angiotensinconverting enzyme (bottom). The design of the dipeptidyl derivative that led to the discovery of captopril is shown bound to the latter enzyme.

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. 

The discovery of teprotide led to a search for new, specific, orally active ACE inhibitors. Ondetti et al. (172) proposed a hypothetical model of the active site of ACE, based on analogy with pancreatic carboxypeptidase A, and used it to predict and design compounds that would occupy the carboxy-terminal binding site of the enzyme. Carboxyalkanoyland mer-captoalkanoyl derivatives of proline were found to act as potent, specific inhibitors of ACE and 2-D-methyl-3-mercaptopropanoyl-L-proline (131) (captopril) was developed and launched in 1981 as an orally active treatment for patients with severe or advanced hypertension. Captopril, modeled on the biologically active peptides found in the venom of the pit viper, made an important contribution to the understanding of hypertension and paved the... 

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... 

Interestingly, the successful design of captopril used simple chemical concepts guided by a hypothetical, paper-and-pencil model of substrate and inhibitor binding to the enzyme active site, that had been inferred from the crystal structure of bovine carboxypeptidase A. The X-ray structure of human ACE became available only in 2003, 25 years after the discovery of the captopril class of drugs. While the crystallographic analysis of the ACE complex... 

Dr. David W. Cushman (left) and Dr. Miguel Ondetti (right) developed captopril using a new approach to drug discovery. The captopril team was able to design a molecule with the structure needed to block the active site of the converting angiotensin enzyme (see box 5-A). 

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