Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438)

Léger, Serge; Black, W. Cameron; Deschênes, Denis; Dolman, Sarah J.; Falgueyret, Jean‐Pierre; Gagnon, Marc; Guiral, Sébastien; Huang, Zheng; Guay, Jocelyne; Leblanc, Yves; Li, Chun‐Sing; Massé, Frédéric; Oballa, Renata M.; Zhang, Lei

doi:10.1016/j.bmcl.2009.11.111

Cited by 62 publications

(42 citation statements)

References 17 publications

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“…50 It was based on the optimization of an earlier analog, MF-438. 51 The in vitro profile of 6 was somewhat worse than that of 5 (IC 50 values of 4.9 and 50 nM against rSCD1 and HepG2 cells, respectively). Compound 6 appeared to be slightly more active in vivo -it achieved greater than 90% suppression of oleic acid production at a dose of 1 mg/kg in a mouse liver pharmacodynamic model.…”

Section: Pyridazine Carboxamides and Related Analogsmentioning

confidence: 97%

“…Compound 4 (MF-438) had an IC 50 value of 2.3 nM against rat SCD1, good PK in rodents with bioavailability of 73% and 38% in mice and rats, respectively. 47 It exhibited an ED 50 between 1 and 3 mg/kg in inhibiting mouse liver SCD1 activity, as measured by inhibiting the conversion of 14 C-stearic acid to 14 C-oleic acid.…”

Section: Pyridazine Carboxamides and Related Analogsmentioning

confidence: 99%

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Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu¹

2012

Drug Discovery

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Section: Pyridazine Carboxamides and Related Analogsmentioning

confidence: 97%

Section: Pyridazine Carboxamides and Related Analogsmentioning

confidence: 99%

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu¹

2012

Drug Discovery

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“…Above that temperature, over-chlorination occurred and desired product 16 was contaminated with over-chlorinated impurities that could only be separated with difficulty after repetitive chromatography. Hydrazides 18, prepared from the corresponding esters (17), were condensed with freshly prepared 16. Subsequent cyclization of the diacylhydrazide intermediates on the reactive chloropyridazines to provide the 1,3,4-oxadiazoles (19) was so problematic that initial attempts employing mild conditions such as PPh 3 /C 2 Cl 6 /Et 3 N [33] or TsCl/Et 3 N [34] were disappointing as they produced complex mixtures.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

Uto¹,

Ueno²,

Kiyotsuka³

et al. 2010

European Journal of Medicinal Chemistry

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“…While it is feasible to measure liver target engagement in preclinical species (8)(9)(10), it would be diffi cult to assess this clinically. Thus, to confi rm target engagement of these liver-targeted compounds, we developed a biological assay using a deuterium-labeled exogenous tracer to measure inhibition of SCD1 activity in plasma.…”

Section: Plasma D7-stearic Acid and D7-oleic Acid Extraction And Analmentioning

confidence: 99%

Plasma-based approach to measure target engagement for liver-targeting stearoyl-CoA desaturase 1 inhibitors

Chen

Huang

Leclair

et al. 2011

Journal of Lipid Research

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derived from diet. SCD1 is responsible for the formation of a cis -double bond at the ⌬ 9-position of palmitoyl-and stearoyl-CoA to generate palmitoleic and oleic acids, the main substrates in triglycerides, cholesterol esters, and phospholipids ( Fig. 1 ) ( 4 ). Interestingly, SCD1 activity can be measured from the ratio of SCD1 products over substrates. In the literature, this ratio is generally referred as the desaturation index ( 3 ). There are four mouse SCD isoforms (SCD1, SCD2, SCD3, and SCD4), two rat SCD isoforms (SCD1 and SCD2), and two human SCD isoforms (SCD1 and SCD5) ( 4, 5 ). Although SCD1 is ubiquitously expressed, it is predominant in liver and adipose tissues. These tissues are the principal sites of de novo lipogenesis, as they have a high capacity to convert carbohydrates into fatty acids when glycolytic and lipogenic enzymes are induced and activated. Targeted deletion of the SCD1 gene in mice has shown that this enzyme is important for lipid homeostasis and body weight regulation ( 6 ). Thus, it is postulated that the inhibition of SCD1 should reduce lipid synthesis and storage, which would be benefi cial for the treatment of diabetes and dyslipidemia.We previously reported that inhibition of SCD in skin and eye leads to adverse events, consisting of dry eye, squinting, and alopecia. These adverse events are observed when systemic SCD inhibitors are used, and they are believed to be mechanism-based due to depletion of essential SCD-derived lubricating lipids. To achieve a therapeutic window for SCD inhibition, a liver-targeting strategy was employed to target the SCD inhibitor to the organ believed to be responsible for the therapeutic effi cacy (liver), while minimizing its exposure in the tissues (skin and eye) associated with adverse events ( 7-10 ). The goal was achieved by designing MK-8245, a liver-targeted SCD inhibitor believed to inhibit the SCD enzyme solely in the liver and not in other tissues for the reasons that follow. When SCD inhibition was measured by the desaturation index in tissues of rodents treated with MK-8245, the desaturation index Abstract A positive correlation between stearoyl-CoA desaturase (SCD)1 expression and metabolic diseases has been reported in rodents and humans. These fi ndings indicate that SCD1 is a promising therapeutic target for the chronic treatment of diabetes and dyslipidemia. The SCD1 enzyme is expressed at high levels in several human tissues and is required for the biosynthesis of monounsaturated fatty acids, which are involved in many biological processes. Liver-targeted SCD inhibitors were designed to pharmacologically manipulate SCD1 activity in the liver to avoid adverse events due to systemic inhibition. This article describes the development of a plasma-based SCD assay to assess the level of SCD inhibition, which is defi ned in this article as target engagement. Essentially, animals are dosed with an exogenous deuterated tracer (d7-stearic acid) as substrate, and the converted d7-oleic acid product is measured to monitor SCD1 inhibitio...

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Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438)

Cited by 62 publications

References 17 publications

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

Plasma-based approach to measure target engagement for liver-targeting stearoyl-CoA desaturase 1 inhibitors

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