Selective SOSA approach

The SOSA approach (SOSA = Selective Optimization of Side Activities) represents an original alternative to high-throughput screening (HTS) [29-31]. SOSA consists of two steps ... 

Fig. 1.16 A successful SOSA approach allowed the identification of the antibacterial sulfonamide sulfathiazole as a ligand of the endothelin ETfl receptor and its optimization to the selective and potent compounds BMS-182874, BMS-193884, and BMS-207940 [34,35],...

A new strategy in drug discovery, the selective optimization of side activities (the SOSA approach), has been formulated by Camille Wermuth [17,18 cf. Chapter I—1], In this approach, minor side activities of active compounds serve as the starting point for structural variations, ultimately to obtain analogues that now have the former side effect as their main activity. In this manner, nanomolar acetylcholinesterase (AChE) inhibitors as well as nanomolar muscarinic M, receptor and 5-HT3 receptor ligands could be derived from the antidepressant minaprine [17,18],... 

Wermuth, C. G. Selective optimization of side activities the SOSA approach. Drug Discov. Today 2006, 11, 160-164. 

Among them, a typical illustration of the SOSA approach is shown by the development of a selective ligand for the endotheline ETa receptors by scientists from Bristol-Myers-Squibb. " Starting from an in-house library, the antibacterial compound sulfathiazole (Fig. 5.13) was an initial, but weak, hit (IC50 = 69 p,M). Testing of related sulfonamides identified the more potent sulfisoxazole (IC50 = 0.78 xM). Systematic variations led finally to the potent and selective... 

Modification of molecules that have already been safely used in humans conduct to compounds with more predictable and less complex pharmacokinetics, lower incidence of side effects, and less demanding clinical studies [36]. On the basis of these considerations, the authors selected for sulfation several flavonoid glycosides already used in human therapy as venotropic agents [103] (Figure 9.23c). This strategy follows the principles of SOSA approach [36,37]. 

Besides the presented methods there are a lot of other ways to generate hits in pharmaceutical industry. Methods like SOSA (selective optimization of side activities) [16] and fragment-based approaches are presented in other chapters and are therefore not discussed here. We have tried to provide an overview of the most often used - at least from our viewpoint - lead generation method in this chapter. It is the authors experience that no single lead generation method... 

---