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. 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

Johan D Oslob  1 , Russell J Johnson  1 , Haiying Cai  1 , Shirley Q Feng  1 , Lily Hu  1 , Yuko Kosaka  1 , Julie Lai  1 , Mohanram Sivaraja  1 , Samnang Tep  1 , Hanbiao Yang  1 , Cristiana A Zaharia  1 , Marc J Evanchik  1 , Robert S McDowell  1
Affiliations

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. .

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.

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Figures

Chart 1
Chart 1. Inhibitors of FASN
Scheme 1
Scheme 1. Compound Progression Leading to Imidazopyridine Motif
Scheme 2
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.
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