362467-58-1Relevant academic research and scientific papers
Efforts towards an On-Target Version of the Groebke–Blackburn–Bienaymé (GBB) Reaction for Discovery of Druglike Urokinase (uPA) Inhibitors
Gladysz, Rafaela,Vrijdag, Johannes,Van Rompaey, Dries,Lambeir, Anne-Marie,Augustyns, Koen,De Winter, Hans,Van der Veken, Pieter
, p. 12380 - 12393 (2019)
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.
Discovery and SAR of novel and selective inhibitors of urokinase plasminogen activator (uPA) with an imidazo[1,2-A]pyridine scaffold
Gladysz, Rafaela,Adriaenssens, Yves,De Winter, Hans,Joossens, Jurgen,Lambeir, Anne-Marie,Augustyns, Koen,Van Der Veken, Pieter
, p. 9238 - 9257 (2015/12/23)
Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's S1 pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-A]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design.
