Inhibitor design process

A number of chemical approaches have been used in the design of renin inhibitors. In the absence of the purified enzyme, most of the early search for inhibitors was carried out using crude renin preparations. The amino acid sequences of mouse, rat and human renin were obtained later on using either the traditional isolation and sequencing techniques or cDNA methodology. Various three-dimensional models of renin were constructed in the early stages, based on the x ray structures of other similar aspartyl proteases, for example endothia-pepsin and penicillopepsin. Later on, the X ray crystal structure of recombinant human renin was reported. The inhibitor design process has been based on some of these models. 

This, and the recruitment of common ions such as chloride, should be regarded as the norm and taken into account in the inhibitor design process. Ladbury [59] has analyzed the way inhibitors recruit water molecules but concluded that at present it is difficult to predict such behavior. 

Often, crystallography is used as a tool for improving inhibitors that already exist. It can be quite difficult to rationally design an inhibitor from scratch, but improvements to known inhibitors can be easily and rapidly modeled. Potential improved inhibitors can then be designed and tested. This can be an iterative process with subsequent rounds of inhibitors designed from each subsequent improvement. 

One of the inhibitors designed during the drug discovery process, 9-(3-pyridylmethy)-9-deazaguanine (BCX-34), was selected for initial clinical development. Current clinical trials utilize both topical and oral formulations of the drug. 

Our iterative ion channel library design process is outlined in Figure 8.13. Retrieval and critical review of literature and in-house data on ion channel modulators resulted in a collection of valuable lead compounds, suitable for 2D and 3D database mining in internal and external compound collections. Among others, we took into account calcium channel blockers like Clonidine, chloride channel blockers, potassium channel openers, K(ATP) channel blocker and openers (e.g., Glibenclamide), and NHE-1 inhibitors. 

Catacarb Process [667], [681], [682]. This process was introduced about 30 years ago. A modified potassium salt solution is used, containing various stable and non toxic catalysts and corrosion inhibitors. The process is very versatile and allows the process and mechanical configuration to be tailored to a wide range of C02 partial pressures. Figure 68 showes a Catacarb single-stage low heat design. 

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