Discovery of atrop fixed alkoxy-aminobenzhydrol derivatives: Novel, highly potent and orally efficacious squalene synthase inhibitors

Bioorganic and Medicinal Chemistry

Volumn 19, Issue 17, 2011, Pages 5207-5224

  Ichikawa, Masanori ^a   Yokomizo, Aki ^a   Itoh, Masao ^a   Haginoya, Noriyasu ^a   Sugita, Kazuyuki ^b   Usui, Hiroyuki ^a   Terayama, Koji ^a   Kanda, Akira ^a  

^a DAIICHI SANKYO CO   (Japan)

^b UNIVERSITY OF TOKYO   (Japan)

Author keywords

Atropisomer; Hypercholesterolemia; Lipid lowering effect; Squalene synthase inhibitor

Indexed keywords

1 [4 [[2,4 DICHLORO 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 (2,2 DIMETHOXYPROPOXY) 6 [HYDROXY(2METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 (3 HYDROXY 2,2 DIMETHYLPROPOXY) 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (3 HYDROXY 3 METHYLBUTOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (3 HYDROXY 3 METHYLBUTOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (3 HYDROXYPROPOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (HYDROXYPROPOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (PROPAN 2 YLOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHOXYPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHOXYPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 4 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHYLPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 ETHOXY 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLIC ACID; 1 [4 [[4 CHLORO 2 ETHOXY 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 4 CARBOXYLIC ACID; ALCOHOL DERIVATIVE; ALKOXYAMINOBENZHYDROL DERIVATIVE; ATORVASTATIN; ETHYL 1 [4 [[2,4 DICHLORO 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 (2,2 DIMETHYLPROPOXY) 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 (3 HYDROXY 2,2 DIMETHYLPROPOXY) 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 (PROPAN 2 YLOXY)PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHOXYPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHOXYPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 4 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 [HYDROXY(2 METHOXYPHENYL)METHYL] 6 METHYLPHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 ETHOXY 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 3 CARBOXYLATE; ETHYL 1 [4 [[4 CHLORO 2 ETHOXY 6 [HYDROXY(2 METHOXYPHENYL)METHYL]PHENYL](2,2 DIMETHYLPROPYL)AMINO] 4 OXOBUTANOYL]PIPERIDINE 4 CARBOXYLATE; SQUALENE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL SYNTHESIS; CONTROLLED STUDY; DRUG EFFECT; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; IC 50; IN VIVO STUDY; ISOMERIZATION; LIVER CELL; MALE; MORNING DOSAGE; NONHUMAN; RAT; REPEATED DRUG DOSE; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTICHOLESTEREMIC AGENTS; BENZHYDRYL COMPOUNDS; BINDING SITES; CALLITHRIX; COMPUTER SIMULATION; CRICETINAE; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; FEMALE; HEPATOCYTES; ISOMERISM; MALE; MODELS, ANIMAL; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA; RATTUS;

EID: 84860389049     PISSN: 09680896     EISSN: 14643391     Source Type: Journal    
DOI: 10.1016/j.bmc.2011.07.007     Document Type: Article

References (22)

1. M.S. Brown, and J.L. Goldstein Cell 89 1997 331
2. M.S. Brown, and J.L. Goldstein Proc. Natl. Acad. Sci. U.S.A. 96 1999 11041
3. J.A. Tobert Nat. Rev. Drug Disc. 2 2003 517
4. R.J. Havel, and E. Rapaport New Eng. J. Med. 332 1995 1491
5. J. Shepherd N. Engl. J. Med. 333 1995 1301
6. I. Abe, J.C. Tomesch, S. Wattanasin, and G.D. Prestwich Nat. Prod. Rep. 11 1994 279
7. S.H. Rosenberg Expert Opin. Ther. Pat. 8 1998 521
8. T. Ishihara, H. Kakuta, H. Moritani, T. Ugawa, and I. Yanagisawa Bioorg. Med. Chem. 12 2004 5899
9. T. Ishihara, H. Kakuta, H. Moritani, T. Ugawa, S. Sakamoto, S. Tsukamoto, and I. Yanagisawa Bioorg. Med. Chem. 11 2003 2403
10. T. Miki, M. Kori, H. Mabuchi, R. Tozawa, T. Nishimoto, Y. Sugiyama, K. Teshima, and H. Yukimasa J. Med. Chem. 45 2002 4571
11. T. Miki, M. Kori, H. Mabuchi, H. Banno, R. Tozawa, M. Nakamura, S. Itokawa, Y. Sugiyama, and H. Yukimasa Bioorg. Med. Chem. 10 2002 401
12. S.A. Biller, K. Neuenschwander, M.M. Ponpipom, and C.D. Poulter Curr. Pharm. Des. 2 1996 1
13. D. Gonzalez-Pacanowska, B. Arison, C.M. Havel, and J.A. Watson J. Biol. Chem. 263 1988 1301
14. J.D. Bergstrom, M.M. Kurtz, D.J. Rew, A.M. Amend, J.D. Karakas, R.G. Bostedor, V.S. Bansal, C. Dufresne, F.L. VanMiddlesworth, and O.D. Hensens Proc. Natl. Acad. Sci. U.S.A. 90 1993 80
15. R.G. Bostedor, J.D. Karkas, B.H. Arison, V.S. Bansal, S. Vaidya, J.I. Germershausen, M.M. Kurtz, and J.D. Bergstrom J. Biol. Chem. 272 1997 9197
16. C. Hodel Toxicol. Lett. 128 2002 159
17. P.D. Thompson, P. Clarkson, and R.H. Karas JAMA 289 2003 1681
18. H. Hiyoshi, M. Yanagimachi, M. Ito, T. Saeki, I. Yoshida, T. Okada, H. Ikuta, D. Shinmyo, K. Tanaka, N. Kurusu, and H. Tanaka Euro. J. Pharmacol. 431 2001 345
19. T. Ugawa, H. Kakuta, H. Moritani, K. Matsuda, T. Ishihara, M. Yamaguchi, S. Naganuma, Y. Iizumi, and H. Shikama Br. J. Pharmacol. 131 2000 63
20. M. Ichikawa, A. Yokomizo, M. Itoh, K. Sugita, H. Usui, H. Shimizu, M. Suzuki, K. Terayama, and A. Kanda Bioorg. Med. Chem. 19 2011 1930 1949
21. The atomic coordinates have been deposited with Protein Data Bank (PDB code: 3ASX).
22. T. Nishimoto Br. J. Pharmacol. 139 2003 911