Acylthiourea, acylurea, and acylguanidine derivatives with potent Hedgehog inhibiting activity

Journal of Medicinal Chemistry

Volumn 55, Issue 4, 2012, Pages 1559-1571

  Solinas, Antonio ^a   Faure, Hélène ^b   Roudaut, Hermine ^b   Traiffort, Elisabeth ^b   Schoenfelder, Angèle ^c   Mann, André ^c   Manetti, Fabrizio ^a   Taddei, Maurizio ^a   Ruat, Martial ^b  

^a UNIVERSITY OF SIENA   (Italy)

^b CNRS   (France)

^c UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLGUANIDINE DERIVATIVE; ACYLTHIOUREA DERIVATIVE; ACYLUREA DERIVATIVE; ANTINEOPLASTIC AGENT; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; HUMAN; HUMAN CELL; HYDROGEN BOND; IC 50; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL DIFFERENTIATION; CELLS, CULTURED; CEREBELLUM; GUANIDINES; HEDGEHOG PROTEINS; HUMANS; HYDROGEN BONDING; MESENCHYMAL STROMAL CELLS; MICE; MODELS, MOLECULAR; OSTEOBLASTS; PLURIPOTENT STEM CELLS; RATS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; THIOUREA; UREA;

EID: 84857402868     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2013369     Document Type: Article

References (46)

1. Dessaud, E.; McMahon, A. P.; Briscoe, J. Pattern formation in the vertebrate neural tube: a Sonic Hedgehog morphogen-regulated transcriptional network Development 2008, 135, 2489-2503
2. Traiffort, E.; Angot, E.; Ruat, M. Sonic Hedgehog signaling in the mammalian brain J. Neurochem. 2010, 113, 576-590
3. Ruat, M.; Roudaut, H.; Ferent, J.; Traiffort, E. Hedgehog trafficking, cilia and brain functions Differentiation 2012, 83, S97-S104
4. Philipp, M.; Caron, M. G. Hedgehog signaling: is Smo a G protein-coupled receptor? Curr. Biol. 2009, 19, R125-R127
5. Barakat, M. T.; Humke, E. W.; Scott, M. P. Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer Trends Mol. Med. 2010, 16, 337-348
6. Tian, H.; Callahan, C. A.; DuPree, K. J.; Darbonne, W. C.; Ahn, C. P.; Scales, S. J.; de Sauvage, F. J. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4254-4259
7. Nieuwenhuis, E.; Hui, C. C. Hedgehog signaling and congenital malformations Clin. Genet. 2005, 67, 193-208 (Pubitemid 40277900)
8. Traiffort, E.; Dubourg, C.; Faure, H.; Rognan, D.; Odent, S.; Durou, M. R.; David, V.; Ruat, M. Functional characterization of Sonic Hedgehog mutations associated with holoprosencephaly J. Biol. Chem. 2004, 279, 42889-42897 (Pubitemid 39372179)
9. Teglund, S.; Toftgard, R. Hedgehog: beyond medulloblastoma and basal cell carcinoma Biochim. Biophys. Acta 2010, 1805, 181-208
10. Berman, D. M.; Karhadkar, S. S.; Hallahan, A. R.; Pritchard, J. I.; Eberhart, C. G.; Watkins, D. N.; Chen, J. K.; Cooper, M. K.; Taipale, J.; Olson, J. M.; Beachy, P. A. Medulloblastoma growth inhibition by Hedgehog pathway blockade Science 2002, 297, 1559-1561 (Pubitemid 34971004)
11. Miller-Moslin, K.; Peukert, S.; Jain, R. K.; McEwan, M. A.; Karki, R.; Llamas, L.; Yusuff, N.; He, F.; Li, Y.; Sun, Y.; Dai, M.; Perez, L.; Michael, W.; Sheng, T.; Lei, H.; Zhang, R.; Williams, J.; Bourret, A.; Ramamurthy, A.; Yuan, J.; Guo, R.; Matsumoto, M.; Vattay, A.; Maniara, W.; Amaral, A.; Dorsch, M.; Kelleher, J. F., III. 1-Amino-4-benzylphthalazines as orally bioavailable Smoothened antagonists with antitumor activity J. Med. Chem. 2009, 52, 3954-3968
12. Pan, S.; Wu, X.; Jiang, J.; Gao, W.; Wan, Y.; Cheng, D.; Han, D.; Liu, J.; Englund, N. P.; Wang, Y.; Peukert, S.; Miller-Moslin, K.; Yuan, J.; Guo, R.; Matsumoto, M.; Vattay, A.; Jiang, Y.; Tsao, J.; Sun, F.; Pferdekamper, A. C.; Dodd, S.; Tuntland, T.; Maniara, W.; Kelleher, J. F.; Yao, Y.-m.; Warmuth, M.; Williams, J.; Dorsch, M. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist ACS Med. Chem. Lett. 2010, 1, 130-134
13. Peukert, S.; Miller-Moslin, K. Small-molecule inhibitors of the hHedgehog signaling pathway as cancer therapeutics ChemMedChem 2010, 5, 500-512
14. ClinicalTrials.gov; National Institutes of Health: Bethesda, MD; http://clinicaltrials.gov/ct2/results?term=GDC-0449 (accessed Feb 6, 2012).
15. Rudin, C. M.; Hann, C. L.; Laterra, J.; Yauch, R. L.; Callahan, C. A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S. E.; Coleman, B.; LoRusso, P. M.; Von Hoff, D. D.; de Sauvage, F. J.; Low, J. A. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449 N. Engl. J. Med. 2009, 361, 1173-1178
16. Von Hoff, D. D.; Lorusso, P. M.; Rudin, C. M.; Reddy, J. C.; Yauch, R. L.; Tibes, R.; Weiss, G. J.; Borad, M. J.; Hann, C. L.; Brahmer, J. R.; Mackey, H. M.; Lum, B. L.; Darbonne, W. C.; Marsters, J. C.; de Sauvage, F. J.; Low, J. A. Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma N. Engl. J. Med. 2009, 361, 1164-1172
17. Yauch, R. L.; Dijkgraaf, G. J.; Alicke, B.; Januario, T.; Ahn, C. P.; Holcomb, T.; Pujara, K.; Stinson, J.; Callahan, C. A.; Tang, T.; Bazan, J. F.; Kan, Z.; Seshagiri, S.; Hann, C. L.; Gould, S. E.; Low, J. A.; Rudin, C. M.; de Sauvage, F. J. Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma Science 2009, 326, 572-574
18. Dijkgraaf, G. J.; Alicke, B.; Weinmann, L.; Januario, T.; West, K.; Modrusan, Z.; Burdick, D.; Goldsmith, R.; Robarge, K.; Sutherlin, D.; Scales, S. J.; Gould, S. E.; Yauch, R. L.; de Sauvage, F. J. Small molecule inhibition of GDC-0449 refractory Smoothened mutants and downstream mechanisms of drug resistance Cancer Res. 2010, 71, 435-444
19. Buonamici, S.; Williams, J.; Morrissey, M.; Wang, A.; Guo, R.; Vattay, A.; Hsiao, K.; Yuan, J.; Green, J.; Ospina, B.; Yu, Q.; Ostrom, L.; Fordjour, P.; Anderson, D. L.; Monahan, J. E.; Kelleher, J. F.; Peukert, S.; Pan, S.; Wu, X.; Maira, S. M.; Garcia-Echeverria, C.; Briggs, K. J.; Watkins, D. N.; Yao, Y. M.; Lengauer, C.; Warmuth, M.; Sellers, W. R.; Dorsch, M. Interfering with resistance to Smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma Sci. Transl. Med. 2010, 2, 51ra70
20. Manetti, F.; Faure, H.; Roudaut, H.; Gorojankina, T.; Traiffort, E.; Schoenfelder, A.; Mann, A.; Solinas, A.; Taddei, M.; Ruat, M. Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonists Mol. Pharmacol. 2010, 78, 658-665
21. Hallur, G.; Jimeno, A.; Dalrymple, S.; Zhu, T.; Jung, M. K.; Hidalgo, M.; Isaacs, J. T.; Sukumar, S.; Hamel, E.; Khan, S. R. Benzoylphenylurea sulfur analogues with potent antitumor activity J. Med. Chem. 2006, 49, 2357-2360
22. Okada, H.; Koyanagi, T.; Yamada, N.; Haga, T. Synthesis and antitumor activities of novel benzoylphenylurea derivatives Chem. Pharm. Bull. (Tokyo) 1991, 39, 2308-2315
23. Klabunde, T.; Wendt, K. U.; Kadereit, D.; Brachvogel, V.; Burger, H. J.; Herling, A. W.; Oikonomakos, N. G.; Kosmopoulou, M. N.; Schmoll, D.; Sarubbi, E.; von Roedern, E.; Schonafinger, K.; Defossa, E. Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes J. Med. Chem. 2005, 48, 6178-6193 (Pubitemid 41428973)
24. Furuta, T.; Sakai, T.; Senga, T.; Osawa, T.; Kubo, K.; Shimizu, T.; Suzuki, R.; Yoshino, T.; Endo, M.; Miwa, A. Identification of potent and selective inhibitors of PDGF receptor autophosphorylation J. Med. Chem. 2006, 49, 2186-2192
25. Haynes, N. E.; Corbett, W. L.; Bizzarro, F. T.; Guertin, K. R.; Hilliard, D. W.; Holland, G. W.; Kester, R. F.; Mahaney, P. E.; Qi, L.; Spence, C. L.; Tengi, J.; Dvorozniak, M. T.; Railkar, A.; Matschinsky, F. M.; Grippo, J. F.; Grimsby, J.; Sarabu, R. Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2 R)-3-cyclopentyl-2- (4-methanesulfonylphenyl)- N -thiazol-2-yl-propionamide (RO0281675) J. Med. Chem. 2010, 53, 3618-3625
26. Keller, M.; Pop, N.; Hutzler, C.; Beck-Sickinger, A. G.; Bernhardt, G.; Buschauer, A. Guanidine-acylguanidine bioisosteric approach in the design of radioligands: synthesis of a tritium-labeled N(G)-propionylargininamide ([3H]-UR-MK114) as a highly potent and selective neuropeptide Y Y1 receptor antagonist J. Med. Chem. 2008, 51, 8168-8172
27. Kleinmaier, R.; Keller, M.; Igel, P.; Buschauer, A.; Gschwind, R. M. Conformations, conformational preferences, and conformational exchange of N ′-substituted N -acylguanidines: intermolecular interactions hold the key J. Am. Chem. Soc. 2010, 132, 11223-11233
28. Narasimhamurthy, N.; Samuelson, A. G. Thiocarbonyl to carbonyl group transformation using CuCl and NaOH Tetrahedron Lett. 1986, 27, 3911-3912
29. Shinada, T.; Umezawa, T.; Ando, T.; Kozuma, H.; Ohfune, Y. A new entry for the synthesis of N -acyl- N ′-substituted guanidines Tetrahedron Lett. 2006, 47, 1945-1947 (Pubitemid 43246902)
30. Daga, M. C.; Taddei, M.; Varchi, G. Rapid microwave-assisted deprotection of N-Cbz and N-Bn derivatives Tetrahedron Lett. 2001, 5191-5194 (Pubitemid 32635124)
31. Bellamy, F. D.; Ou, K. Selective reduction of aromatic nitro compounds with stannous chloride in nonacidic and nonaqueous medium Tetrahedron Lett. 1984, 25, 839-842 (Pubitemid 14186580)
32. Rasmussen, C. R.; Villani, J. F. J.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Powell, E. T.; Molinari, A. J. Improved Procedures for the Preparation of Cycloalkyl-, Arylalkyl-, and Arylthioureas Synthesis 1988, 456-459
33. Yang, G.; Chen, Z.; Zhang, H. Clean synthesis of an array of N -benzoyl- N ′-aryl ureas using polymer-supported reagents Green Chem. 2003, 441-442
34. Taipale, J.; Chen, J. K.; Cooper, M. K.; Wang, B.; Mann, R. K.; Milenkovic, L.; Scott, M. P.; Beachy, P. A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine Nature 2000, 406, 1005-1009
35. Hyman, J. M.; Firestone, A. J.; Heine, V. M.; Zhao, Y.; Ocasio, C. A.; Han, K.; Sun, M.; Rack, P. G.; Sinha, S.; Wu, J. J.; Solow-Cordero, D. E.; Jiang, J.; Rowitch, D. H.; Chen, J. K. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 14132-14137
36. Masdeu, C.; Faure, H.; Coulombe, J.; Schoenfelder, A.; Mann, A.; Brabet, I.; Pin, J. P.; Traiffort, E.; Ruat, M. Identification and characterization of Hedgehog modulator properties after functional coupling of Smoothened to G15 Biochem. Biophys. Res. Commun. 2006, 349, 471-479 (Pubitemid 44363055)
37. Chen, J. K.; Taipale, J.; Young, K. E.; Maiti, T.; Beachy, P. A. Small molecule modulation of Smoothened activity Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14071-14076 (Pubitemid 35257626)
38. Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. Privileged molecules for protein binding identified from NMR-based screening J. Med. Chem. 2000, 43, 3443-3447
39. Patel, K. M.; Patel, H. A.; Sen, D. J.; Panigrahi, B. B.; Badmanaban, R. In vitro evaluation of total reducing property of the synthesized molecule having variable atomic electronegativity J. Chem. Pharm. Res. 2010, 2, 631-639
40. Goodrich, L. V.; Milenkovic, L.; Higgins, K. M.; Scott, M. P. Altered neural cell fates and medulloblastoma in mouse Patched mutants Science 1997, 277, 1109-1113 (Pubitemid 27371635)
41. Romer, J. T.; Kimura, H.; Magdaleno, S.; Sasai, K.; Fuller, C.; Baines, H.; Connelly, M.; Stewart, C. F.; Gould, S.; Rubin, L. L.; Curran, T. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(±)p53(-/-) mice Cancer Cell 2004, 6, 229-240 (Pubitemid 39222036)
42. Charytoniuk, D.; Porcel, B.; Rodriguez Gomez, J.; Faure, H.; Ruat, M.; Traiffort, E. Sonic Hedgehog signalling in the developing and adult brain J. Physiol. (Paris) 2002, 96, 9-16 (Pubitemid 34087028)
43. Chen, J. K.; Taipale, J.; Cooper, M. K.; Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened Genes Dev. 2002, 16, 2743-2748 (Pubitemid 35253140)
44. Roudaut, H.; Traiffort, E.; Gorojankina, T.; Vincent, L.; Faure, H.; Schoenfelder, A.; Mann, A.; Manetti, F.; Solinas, A.; Taddei, M.; Ruat, M. Identification and mechanism of action of the acylguanidine MRT-83, a novel potent Smoothened antagonist Mol. Pharmacol. 2011, 79, 453-460
45. Rominger, C. M.; Bee, W. L.; Copeland, R. A.; Davenport, E. A.; Gilmartin, A.; Gontarek, R.; Hornberger, K. R.; Kallal, L. A.; Lai, Z.; Lawrie, K.; Lu, Q.; McMillan, L.; Truong, M.; Tummino, P. J.; Turunen, B.; Will, M.; Zuercher, W. J.; Rominger, D. H. Evidence for allosteric interactions of antagonist binding to the Smoothened receptor J. Pharmacol. Exp. Ther. 2009, 329, 995-1005
46. Barnum, D.; Greene, J.; Smellie, A.; Sprague, P. Identification of common functional configurations among molecules J. Chem. Inf. Comput. Sci. 1996, 36, 563-571 (Pubitemid 126539357)