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Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity

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Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy
CNRS, UPR-3294, Laboratoire de Neurobiologie et Développement, Institut de Neurobiologie Alfred Fessard IFR2118, Signal Transduction and Developmental Neuropharmacology Team, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
§ Laboratoire d’Innovation Thérapeutique, UMR-7200, CNRS—Université de Strasbourg, 74 Route du Rhin, F-67401 Illkirch, France
*Phone: +33 1 69 82 36 41. Fax: +33 1 69 82 36 39. E-mail: [email protected] (M.R.); [email protected] (M.T.).
Cite this: J. Med. Chem. 2012, 55, 4, 1559–1571
Publication Date (Web):January 23, 2012
Copyright © 2012 American Chemical Society

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    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.

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    Experimental chemical procedures; analytical data of compounds 2091; comparison tables of AcTU vs corresponding AcU and of AcTU vs corresponding AcG. This material is available free of charge via the Internet at

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