Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility

Bioorganic and Medicinal Chemistry

Volumn 20, Issue 18, 2012, Pages 5507-5517

  Ohashi, Tomohiro ^a   Oguro, Yuya ^a   Tanaka, Toshio ^a   Shiokawa, Zenyu ^a   Tanaka, Yuta ^a   Shibata, Sachio ^a   Sato, Yoshihiko ^a   Yamakawa, Hiroko ^a   Hattori, Harumi ^a   Yamamoto, Yukiko ^a   Kondo, Shigeru ^a   Miyamoto, Maki ^a   Nishihara, Mitsuhiro ^a   Ishimura, Yoshimasa ^a   Tojo, Hideaki ^a   Baba, Atsuo ^a   Sasaki, Satoshi ^a  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

Hedgehog; Hh signaling inhibitor; Pyrrolo 3,2 c pyridine 4 one; TAK 441

Indexed keywords

3 (2,2 DIFLUOROETHOXY) 6 ETHYL N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; 3 ETHOXY 6 ETHYL N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; 3,6 DIETHYL N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; 6 ETHYL 3 (2 FLUOROETHOXY) N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; 6 ETHYL N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 3 (2,2,2 TRIFLUOROETHOXY) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; 6 ETHYL N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 3 METHOXY 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; ANTINEOPLASTIC AGENT; MESSENGER RNA; N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 3 METHOXY 1 METHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5,6,7,8,9 HEXAHYDRO 1H PYRROLO[3,2 C]QUINOLINE 2 CARBOXAMIDE; N [1 (HYDROXYACETYL)PIPERIDIN 4 YL] 3 METHOXY 1,6 DIMETHYL 4 OXO 5 (2 OXO 2 PHENYLETHYL) 4,5 DIHYDRO 1H PYRROLO[3,2 C]PYRIDINE 2 CARBOXAMIDE; PROTEIN INHIBITOR; PYRROLO[3,2 C]PYRIDINE DERIVATIVE; SONIC HEDGEHOG PROTEIN; TAK 441; TRANSCRIPTION FACTOR GLI1; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG DOSE COMPARISON; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; GENE; GLI1 GENE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MEDULLOBLASTOMA; MOUSE; NONHUMAN; PLASMA CONCENTRATION-TIME CURVE; RAT; TUMOR VOLUME; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HEDGEHOG PROTEINS; HUMANS; KRUPPEL-LIKE TRANSCRIPTION FACTORS; MEDULLOBLASTOMA; MICE; MICE, NUDE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NIH 3T3 CELLS; PYRIDINES; PYRROLES; RNA, MESSENGER; SIGNAL TRANSDUCTION; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HOMOLOGOUS;

ERINACEIDAE;

EID: 84866234204     PISSN: 09680896     EISSN: 14643391     Source Type: Journal    
DOI: 10.1016/j.bmc.2012.07.034     Document Type: Article

References (8)

1. 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. Bioorg. Med. Chem. in press. http://dx.doi.org/10.1016/j. bmc.2012.07.039.
2. M. Ishikawa, and K. Ajito Y. Torisawa, Soyaku Shien Kenkyu no Tenbo 2008 CMC Publishing Tokyo 3 13
3. Y. Fujita, M. Yonehara, M. Tetsuhashi, T. Noguchi-Yachide, Y. Hashimoto, and M. Ishikawa Bioorg. Med. Chem. Lett. 18 2010 1194
4. D.F. Dropinski, T. Akiyama, M. Einstein, B. Habulihaz, T. Doebber, J.P. Berger, P.T. Meinke, and G.Q. Shi Bioorg. Med. Chem. Lett. 15 2005 5035
5. B. Hans-Joachim, B. David, B. Stefanie, K. Manfred, K. Bernd, M. Klaus, O. Ulrike, and S. Martin ChemBioChem 5 2004 637
6. K.H. William J. Med. Chem. 51 15 2008 4359
7. X-ray crystallographic data for compound 11d has been deposited with the Cambridge Crystallographic Data Center as CCDC 865214. The crystallographic data can be obtained, free of charge, on application to CCDC; 12 Union Road, Cambridge CB2 1EZ, UK.
8. K. Sasai, J.T. Romer, Y. Lee, D. Finkelstein, C. Fuller, P.J. McKinnon, and T. Curran Cancer Res. 66 2006 4215