Efforts towards an On‐Target Version of the Groebke–Blackburn–Bienaymé (GBB) Reaction for Discovery of Druglike Urokinase (uPA) Inhibitors. Issue 53 (29th August 2019) - Gladysz, Rafaela
Abstract: Target‐guided synthesis (TGS) has emerged as a promising strategy in drug discovery. Although reported examples of TGS generally involve two‐component reactions, there is a strong case for developing target‐guided versions of three‐component reactions (3CRs) because of their potential to deliver highly diversified druglike molecules. To this end, the Groebke–Blackburn–Bienaymé reaction was selected as a model 3CR. We recently reported a series of druglike urokinase inhibitors, and these serve as reference compounds in the present study. Due to the limited number of literature reports on target‐guided 3CRs, multiple experimental parameters were optimized here. Most challenging was the formation of imine intermediates under near‐physiological conditions. This aspect was addressed by exploring chemical imine stabilization strategies. Notably, imines are also crucial intermediates of other 3CRs. Such systematic studies are strongly required for further development of the TGS domain but are largely absent in the literature. Hence, this work is intended as a reference for future multicomponent‐based TGS studies. Abstract : Target‐guided inhibitor assembly : While examples of target‐guided synthesis (TGS) generally involve two‐component reactions, we selected the Groebke–Blackburn–Bienaymé reaction as a model three‐component reaction affording urokinase inhibitors (see graphic). Multiple experimental parameters have been optimized. Additionally, chemical imine stabilization strategies have been explored. Since imines are also crucial intermediates of other multicomponent reactions, this work is intended as a reference for future multicomponent‐based TGS studies.