1263131-91-4Relevant academic research and scientific papers
Acyl Guanidine Derivatives Modulating The Hedgehog Protein Signaling Pathway
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Page/Page column 18-19, (2012/08/08)
The present invention relates to acyl guanidine derivatives modulating the hedgehog protein signaling pathway to be used as drugs, in particular for treating diseases involving a tissue dysfunction associated with a deregulation of the hedgehog protein signaling pathway, as well as to pharmaceutical compositions containing same. The present invention also relates to novel acyl guanidine derivatives as such.
Acylthiourea, acylurea, and acylguanidine derivatives with potent Hedgehog inhibiting activity
Solinas, Antonio,Faure, Hélène,Roudaut, Hermine,Traiffort, Elisabeth,Schoenfelder, Angèle,Mann, André,Manetti, Fabrizio,Taddei, Maurizio,Ruat, Martial
supporting information; experimental part, p. 1559 - 1571 (2012/04/17)
The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
