Synthesis and biological evaluation of a novel 3-sulfonyl-8-azabicyclo[3.2. 1]octane class of long chain fatty acid elongase 6 (ELOVL6) inhibitors

Journal of Medicinal Chemistry

Volumn 52, Issue 14, 2009, Pages 4111-4114

  Nagase, Tsuyoshi ^a   Takahashi, Toshiyuki ^a   Sasaki, Takahide ^a   Nagumo, Akira ^a   Shimamura, Ken ^a   Miyamoto, Yasuhisa ^a   Kitazawa, Hidefumi ^a   Kanesaka, Maki ^a   Yoshimoto, Ryo ^a   Aragane, Katsumi ^a   Tokita, Shigeru ^a   Sato, Nagaaki ^a  

^a BANYU PHARMACEUTICAL CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

3 SULFONYL 8 AZABICYCLO[3.2.1]OCTANE; BICYCLO COMPOUND; ENZYME INHIBITOR; HETEROCYCLIC COMPOUND; LONG CHAIN FATTY ACID ELONGASE 6; LONG CHAIN FATTY ACID ELONGASE 6 INHIBITOR; MEMBRANE ENZYME; OCTANE; PALMITOYL COENZYME A; SULFONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME MECHANISM; HIGH THROUGHPUT SCREENING; MALE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ACETYLTRANSFERASES; ANIMALS; CELL LINE; DRUG DESIGN; ENZYME INHIBITORS; HEPATOCYTES; HUMANS; INHIBITORY CONCENTRATION 50; LIVER; MALE; MICE; OCTANES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; TROPANES;

EID: 67650726041     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900488k     Document Type: Article

References (22)

1. Unger, R. H. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003, 144, 5159-5165.
2. Delarue, J.; Magnan, C. Free fatty acids and isuline resistance. Curr. Opin. Clin. Nutr. Metab. Care 2007, 10, 142-148.
3. Cao, H.; Gerhold, K.; Mayers, J. R.; Wiest, M. M.; Watkins, S. M.; Hotamisligil, G. S. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008, 134, 933-944.
4. Matsuzaka, T.; Shimano, H.; Yahagi, N.; Kato, T.; Atsumi, A.; Yamamoto, T.; Inoue, N.; Ishikawa, M.; Okada, S.; Ishigaki, N.; Iwasaki, H.; Iwasaki, Y.; Karasawa, T.; Kumadaki, S.; Matsui, T.; Sekiya, M.; Ohashi, K.; Hasty, A. H.; Nakagawa, Y.; Takahashi, A.; Suzuki, H.; Yatoh, S.; Sone, H.; Toyoshima, H.; Osuga, J.; Yamada, N. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat. Med. 2007, 13, 1193-1202.
5. Shi, Y.; Burn, P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat. Rev. Drug Discovery 2004, 3, 695-710.
6. Moon, Y. A.; Shah, N. A.; Mohapatra, S.; Warrington, J. A.; Horton, J. D. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J. Biol. Chem. 2001, 276, 45358-45366.
7. Matsuzaka, T.; Shimano, H.; Yahagi, N.; Yoshikawa, T.; Amemiya-Kudo, M.; Hasty, A. H.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Ohashi, K.; Osuga, J.; Takahashi, A.; Yato, S.; Sone, H.; Ishibashi, S.; Yamada, N. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs. J. Lipid Res. 2002, 43, 911-920.
8. Fatty acyl-CoA elongation in microsomal fractions requires four sequential steps: (1) condensation between fatty acyl-CoA and malonyl-CoA to generate β-ketoacyl-CoA by ELOVLs, (2) reduction by β-ketoacyl-CoA reductase, (3) dehydrogenase by β-hydroxyacyl-CoA dehydrogenase, and (4) reduction by trans-2,3-enoyl-CoA reductase (see refs 9 and 10). ELOVL enzymes are responsible for the initial condensation reaction, which is rate-limiting in the four sequential steps (see refs 6 and 7).
9. Barrett, P. B.; Harwood, J. L. Characterization of fatty acid elongase enzymes from germinating pea seeds. Phytochemistry 1998, 48, 1295-1304.
10. Nugteren, D. H. The enzymic chain elongation of fatty acids by ratliver microsomes. Biochim. Biophys. Acta 1965, 106, 280-290.
11. Kumadaki, S.; Matsuzaka, T.; Kato, T.; Yahagi, N.; Yamamoto, T.; Okada, S.;Kobayashi, K.; Takahashi, A.; Yatoh, S.; Suzuki, H.; Yamada, N.; Shimano, H. Mouse Elovl-6 promoter is an SREBP target. Biochem. Biophys. Res. Commun. 2008, 368, 261-266.
12. Tvrdik, P.; Asadi, A.; Kozak, L. P.; Nedergaard, J.; Cannon, B.; Jacobsson, A. Cig30, a mouse member of a novel membrane protein gene family, is involved in the recruitment of brown adipose tissue. J. Biol. Chem. 1997, 272, 31738-31746.
13. Tvrdik, P.; Westerberg, R.; Silve, S.; Asadi, A.; Jakobsson, A.; Cannon, B.; Loison, G.; Jacobsson, A. Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids. J. Cell Biol. 2000, 149, 707-718.
14. Zhang, K.; Kniazeva, M.; Han, M.; Li, W.; Yu, Z.; Yang, Z.; Li, Y.; Metzker, M. L.; Allikmets, R.; Zack, D. J.; Kakuk, L. E.; Lagali, P. S.; Wong, P. W.; MacDonald, I. M.; Sieving, P. A.; Figueroa, D. J.; Austin, C. P.; Gould, R. J.; Ayyagari, R.; Petrukhin, K. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat. Genet. 2001, 27, 89-93.
15. Leonard, A. E.; Bobik, E. G.; Dorado, J.; Kroeger, P. E.; Chuang, L. T.; Thurmond, J. M.; Parker-Barnes, J. M.; Das, T.; Huang, Y. S.; Mukerji, P. Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. Biochem. J. 2000, 350, 765-770.
16. Brolinson, A.; Fourcade, S.; Jakobsson, A.; Pujol, A.; Jacobsson, A. Steroid hormones control circadian Elovl3 expression in mouse liver. Endocrinology 2008, 149, 3158-3166.
17. Wang, Y.; Botolin, D.; Xu, J.; Christian, B.; Mitchell, E.; Jayaprakasam, B.; Nair, M.; Peters, J. M.; Busik, J.; Olson, L. K.; Jump, D. B. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J. Lipid Res. 2006, 47, 2028-2041.
18. Miyazaki, M.; Dobrzyn, A.; Man, W. C.; Chu, K.; Sampath, H.; Kim, H. J.; Ntambi, J. M. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J. Biol. Chem. 2004, 279, 25164-25171.
19. Shimamura, K.; Miyamoto, Y.; Kobayashi, T.; Kotani, H.; Tokita, S. Establishment of a high throughput assay for long chain fatty acyl-CoA elongase using homogeneous scintillation proximity assay. Assay Drug Dev. Technol., in press.
20. The detailed experimental procedure for evaluation of metabolic stability inmousemicrosomes is described in Supporting Information.
21. Ntambi, J. M.; Miyazaki, M. J. Recent insights into stearoyl-CoA desaturase-1. Curr. Opin. Lipidol. 2003, 14, 255-261.
22. Nishimura, I.; Hirano, A.; Yamashita, T.; Fukami, T. Improvement of the high-speed logDassay using an injection marker for the water plug aspiration/injection method. J. Chromatogr., A 2009, 1216, 2984-2988.