Soft analog

Soft analogs close structural analogs cf known active drugs that have a specific met-abolically sensitive moiety built into their structure to allow a facile, one-step controllable deactivation and detoxication after the desired therapeutic role has been achieved. 

Figure 15.18. Design and metabolism of soft anticholinergics based on the inactive metabolite-based approach (64, 69 substitutions at two different positions) and the soft analog approach (73). pAg values shown are for in vitro anticholinergic activity determined by guinea pig ileum assay with carbachol as agonist.

Figure 15.19. Cetylpyridinium chloride (76) and soft analog antimicrobials (77, 78). The general hydrolytic deactivation mechanism of soft quaternary salts (79) through a very short-lived intermediate to an acid, an amine, and an aldehyde is also shown.

The simplest example of useful true soft analogs (Fig. 15.19) is provided by the isosteric analogs (77, 78) of cetylpyridinium chloride... 

Fig. 15.21) is an orally active class Ic antiarrhythmic agent that underwent clinical trials and for which a number of soft analogs... 

Figure 15.21. Soft analogs (89)of ACC-9358 (88), an orally activeclassicantiarrhythmic agentthat underwent clinical evaluation. Soft analogs such as (90) and (91) showed good activity and sufficiently short half-life in human blood.

All active soft analog may solve many of these problems, and because amiodarone has a butyl side chain, its structure is well suited for such a design (Fig. 15.22). A number of possi-... 

Figure 15.22. Amiodarone (92)and possible soft analogs (ATI-2000 series, 93), in which the butyl side chain at position 2 of the benzofurane moiety of amiodarone is replaced with an ester-containing side chain to allow facile hydrolytic degradation.

The above examples illustrate the generally applicable isosteric-type soft analog design, where an ester or a reversed ester function replaces two neighboring methylene groups. In some of these cases, when sufficient structural variability is introduced, the distinction between a soft analog and a (real or... 

Figure 15.23. Design and metabolism of ultrashort-acting ACE inhibitors (95) based on soft analogs of captopril (94). Hydrolytic cleavage of these compounds results in small, hydrophilic metabolites (e.g., 97, 98) that have no ACE inhibitory activity.

Perhexiline Analogs. Perhexiline is a Ca + channel blocker that is effective in the treatment of angina pectoris, the most common symptom of chronic ischemic heart disease, but is of limited use because of side effects such as hepatotoxicity, weight loss, and peripheral neuropathy. Given that these undesirable effects are related to the slow metabolism and accumulation of perhexiline, soft analogs may represent a conceivable alternative. A class of analogs with an amide moiety inserted as a possible enzymatically labile cen-... 

Figure 15.24. Design of soft analogs (101, 102) of methotrexate (99) and trimetrexate (100) as possible DHFR inhibitors.

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