- Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series
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Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
- Lachance, Nicolas,Guiral, Sébastien,Huang, Zheng,Leclerc, Jean-Philippe,Li, Chun Sing,Oballa, Renata M.,Ramtohul, Yeeman K.,Wang, Hao,Wu, Jin,Zhang, Lei
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p. 623 - 627
(2012/03/11)
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- NOVEL HETEROAROMATIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) or a pharmaceutically acceptable salt thereof, wherein W is a substituted heteroaryl, X and Y are each independently a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR6-, -C(O)-, -C(CH3)(OH)- or -C(CH3)=CH-, u is an integer from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis, obesity, Type 2 diabetes, insulin resistance, hyperglycemia, Metabolic Syndrome, neurological disease, cancer, and liver steatosis
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