Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

doi:10.1021/ml300335r

. 2012 Dec 2;4(1):113-7.

doi: 10.1021/ml300335r. eCollection 2013 Jan 10.

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Affiliations

PMID: 24900571
PMCID: PMC4027139
DOI: 10.1021/ml300335r

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Johan D Oslob et al. ACS Med Chem Lett. 2012.

. 2012 Dec 2;4(1):113-7.

doi: 10.1021/ml300335r. eCollection 2013 Jan 10.

Affiliation

¹ 3-V Biosciences, Inc. , 1050 Hamilton Court, Menlo Park, California 94025, United States.

PMID: 24900571
PMCID: PMC4027139
DOI: 10.1021/ml300335r

Abstract

Potent imidazopyridine-based inhibitors of fatty acid synthase (FASN) are described. The compounds are shown to have antiviral (HCV replicon) activities that track with their biochemical activities. The most potent analogue (compound 19) also inhibits rat FASN and inhibits de novo palmitate synthesis in vitro (cell-based) as well as in vivo.

Keywords: FASN; HCV; antiviral; in vivo; inhibitor; reversible; structure−activity relationship; target modulation.

PubMed Disclaimer

Figures

**Scheme 1. Compound Progression Leading to Imidazopyridine Motif**

**Scheme 2. Preparation of Compound 19**
Reagents and conditions: (a) NaIO₄, I₂, H₂SO₄, AcOH. (b) n-BuLi, THF, −78 °C, then DMF. (c) 4-(Piperidine-4-yl)benzonitrile, HBTU, DIEA, DMF. (d) Pyrrolidine, K₂CO₃, MeCN, 70 °C (91%). (e) H₂, Pd/C, MeOH (94%). (f) Compound 28, Na₂S₂O₅, DMF, 100 °C.

See this image and copyright information in PMC

Cited by

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.
Alwarawrah Y, Hughes P, Loiselle D, Carlson DA, Darr DB, Jordan JL, Xiong J, Hunter LM, Dubois LG, Thompson JW, Kulkarni MM, Ratcliff AN, Kwiek JJ, Haystead TA. Alwarawrah Y, et al. Cell Chem Biol. 2016 Jun 23;23(6):678-88. doi: 10.1016/j.chembiol.2016.04.011. Epub 2016 Jun 2. Cell Chem Biol. 2016. PMID: 27265747 Free PMC article.
Structural and Synthetic Aspects of Small Ring Oxa- and Aza-Heterocyclic Ring Systems as Antiviral Activities.
Manna S, Das K, Santra S, Nosova EV, Zyryanov GV, Halder S. Manna S, et al. Viruses. 2023 Aug 28;15(9):1826. doi: 10.3390/v15091826. Viruses. 2023. PMID: 37766233 Free PMC article. Review.
Identification of Fasnall as a therapeutically effective Complex I inhibitor.
Mukha D, Dessain J, O'Connor S, Pniewski K, Bertolazzi F, Patel J, Mullins M, Schug ZT. Mukha D, et al. bioRxiv [Preprint]. 2024 May 6:2024.05.03.592013. doi: 10.1101/2024.05.03.592013. bioRxiv. 2024. PMID: 38766222 Free PMC article. Preprint.
Cytotoxicity and Radiosensitizing Activity of the Fatty Acid Synthase Inhibitor C75 Is Enhanced by Blocking Fatty Acid Uptake in Prostate Cancer Cells.
Rae C, Fragkoulis GI, Chalmers AJ. Rae C, et al. Adv Radiat Oncol. 2020 Jun 29;5(5):994-1005. doi: 10.1016/j.adro.2020.06.022. eCollection 2020 Sep-Oct. Adv Radiat Oncol. 2020. PMID: 33083663 Free PMC article.
A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site.
Hardwicke MA, Rendina AR, Williams SP, Moore ML, Wang L, Krueger JA, Plant RN, Totoritis RD, Zhang G, Briand J, Burkhart WA, Brown KK, Parrish CA. Hardwicke MA, et al. Nat Chem Biol. 2014 Sep;10(9):774-9. doi: 10.1038/nchembio.1603. Epub 2014 Aug 3. Nat Chem Biol. 2014. PMID: 25086508

See all "Cited by" articles

References

1. Chirala S. S.; Wakil S. J. Structure and function of animal fatty acid synthase. Lipids 2004, 39111045–1053. - PubMed
1. Liu H.; Liu J. Y.; Wu X.; Zhang J. T. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int. J. Biochem. Mol. Biol. 2010, 1169–89. - PMC - PubMed
1. Kuhajda F. P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000, 163202–208. - PubMed
1. Menendez J. A.; Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 710763–777. - PubMed
1. Abramson H. N. The lipogenesis pathway as a cancer target. J. Med. Chem. 2011, 54165615–5638. - PubMed

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Chemical Information
- BindingDB
Miscellaneous
- NCI CPTAC Assay Portal

[1] Chirala S. S.; Wakil S. J. Structure and function of animal fatty acid synthase. Lipids 2004, 39111045–1053. - PubMed

[2] Chirala S. S.; Wakil S. J. Structure and function of animal fatty acid synthase. Lipids 2004, 39111045–1053. - PubMed

[3] Liu H.; Liu J. Y.; Wu X.; Zhang J. T. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int. J. Biochem. Mol. Biol. 2010, 1169–89. - PMC - PubMed

[4] Liu H.; Liu J. Y.; Wu X.; Zhang J. T. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int. J. Biochem. Mol. Biol. 2010, 1169–89. - PMC - PubMed

[5] Kuhajda F. P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000, 163202–208. - PubMed

[6] Kuhajda F. P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000, 163202–208. - PubMed

[7] Menendez J. A.; Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 710763–777. - PubMed

[8] Menendez J. A.; Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 710763–777. - PubMed

[9] Abramson H. N. The lipogenesis pathway as a cancer target. J. Med. Chem. 2011, 54165615–5638. - PubMed

[10] Abramson H. N. The lipogenesis pathway as a cancer target. J. Med. Chem. 2011, 54165615–5638. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Affiliation

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

Authors

Affiliation

Abstract

Figures

Similar articles

Cited by

References

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Miscellaneous

Abstract

Figures

Similar articles

Cited by

References

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Chemical Information

Miscellaneous