Design, synthesis, and biological study of 6,7-dihydro-5H-pyrano[2,3-d] pyrimidine derivatives as novel hedgehog signaling pathway inhibitors

Medicinal Chemistry Research

Volumn 23, Issue 8, 2014, Pages 3784-3792

  Xin, Minhang ^a,b   Zhang, Liandi ^b   Shen, Han ^b,c   Wen, Jun ^b,c   Tu, Chongxing ^c   Liu, Zhaoyu ^b   Cheng, Lingfei ^b,c   Zhao, Xinge ^b,c  

^a XI'AN JIAOTONG UNIVERSITY   (China)

^b Jiangsu Simcere Pharmaceutical RandD Co Ltd   (China)

^c Nanjing BioSciKin Co Ltd Small Molecule Drug Discovery Platform   (China)

Author keywords

6,7 Dihydro 5H pyrano 2,3 d pyrimidine; Hedgehog signaling pathway; Inhibitors; Novel

Indexed keywords

6,7 DIHYDRO 5H PYRANO[2,3 D]PYRIMIDINE; ANTINEOPLASTIC AGENT; HEDGEHOG SIGNALING PATHWAY INHIBITOR; N (2 METHYL 5 (MORPHOLINO)PHENYL) 4 ((4 (4 (TRIFLUOROMETHOXY)PHENYL) 6,7 DIHYDRO 5H PYRANO[2,3 D]PYRIMIDIN 2 YL)AMINO)BENZAMIDE; N (2,6 DIMETHYLPHENYL) 4 ((4 (4 (TRIFLUOROMETHOXY)PHENYL) 6,7 DIHYDRO 5H PYRANO[2,3 D]PYRIMIDIN 2 YL)AMINO)BENZAMIDE; PYRIMIDINE DERIVATIVE; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG; VISMODEGIB;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG POTENCY; DRUG SYNTHESIS; IN VITRO STUDY; IN VIVO STUDY; MALE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

EID: 84904429186     PISSN: 10542523     EISSN: 15548120     Source Type: Journal    
DOI: 10.1007/s00044-014-0959-3     Document Type: Article

References (14)

1. Bergeron P, Cohen F, Estrada A, Koehler MF, Ly C, Lyssikatos JP, Pei Z, Lee W, Zhao X (2010) Oxo-heterocycle fused pyrimidine compounds, compositions and methods of use. Patent Application US 2010/0331305
2. Dlugosz A, Agrawal S, Kirkpatrick P (2012) Vismodegib. Nat Rev Drug Disc 11:437-438
3. EI-Agrody AM, EI-Latif MS Abd, EI-Hady NA, Fakery AH, Bedair AH (2001) Heteroaromatization with 4-hydroxycoumarin part II: synthesis of some new pyrano[2,3-d]pyrimidines, [1,2,4]triazolo [1,5-c]pyrimidines and pyrimido[1,6-b][1,2,4]triazine derivatives. Molecules 6:519-527
4. Hadden MK (2013) Hedgehog pathway inhibitors: a patent review (2009-present). Exp Opin Ther Pat 23:345-361
5. Herrera A, Martinez-Alvarez R, Ramiro P, Almy J (2006) An easy synthesis of pyranopyrimidines. Monatsh Chem 137:1421-1430 (Pubitemid 44691530)
6. Huang X, Su J, Rao AU, Tang H, Zhou W, Zhu X, Chen X, Liu Z, Huang Y, Degrado S, Xiao D, Qin J, Aslanian R, McKittrick BA, Greenfeder S, Heek MV, Chintala M, Palani A (2012) SAR studies of C2 ether of 2H-pyrano[2,3-d] pyrimidine-2,4,7(1H, 3H) -triones as nicotinic acid receptor (NAR) agonist. Bioorg Med Chem 22:854-858
7. Ng JM, Curran T (2011) The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer 11:493-501
8. Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Shibata S, Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Tojo H, Baba A, Sasaki S (2012) Discovery of pyrrolo[3,2-c] quinoline-4-one derivatives as novel hedgehog signaling inhibitors. Bioorg Med Chem 20:5496-5506
9. Onishi H, Katano M (2011) Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci 102:1756-1760
10. Robarge KD, Brunton SA, Castanedo GE, Cui MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MF, Kotkow K, La H, LaLonde RL, Lau K, Lee L, Marshall D, Marsters JC, Murray LJ, Qian C, Rubin LL, Salphati L, Stanley MS, Stibbard JH, Sutherlin DP, Ubhayaker S, Wang S, Wong S, Xie M (2009) GDC-0449-A potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett 19:5576-5581
11. Ruch JM, Kim EJ (2013) Hedgehog signaling pathway and cancer therapeutics: progress to date. Drugs 73:1-11
12. Xin M, Wen J, Tang F, Tu C, Shen H, Zhao X (2013) The discovery of novel of N-(2-pyrimidinylamino) benzamide derivatives as potent hedgehog signaling pathway inhibitors. Bioorg Med Chem Lett 23:6777-6783
13. Xin M, Wen J, Tang F, Tu C, Huang W, Shen H, Zhao X, Cheng L, Wang M, Zhang L (2014a) Synthesis and evaluation of novel of 4-(2-pyrimidinylamino) benzamides inhibitors of hedgehog signaling pathway. Bioorg Med Chem Lett 24:983-988
14. Xin M, Zhang L, Tang F, Tu C, Wen J, Zhao X, Liu Z, Cheng L, Shen H (2014b) Design, synthesis and evaluation of pyrrolo[2,1-f] [1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors. Bioorg Med Chem 22:1429-1440