Medicinal Chemistry Efforts Reported Prior To 2009

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Several reports of ACC inhibitors have appeared over the last 10 years [20,21]. The natural product soraphen (1) has been shown to be an inhibitor of human ACC2 [22] and human ACC1 [23,24] with IC50's of 2

and 1-5 nM, respectively. Soraphen has also been shown to increase the oxidation rate of 14C-labeled palmitate in Wistar rats and also to increase the percentage of lipid metabolism as measured by respiratory quotient (RQ) [22]. Soraphen has been cocrystallized with the BC domain of yeast ACC and is the only ACC inhibitor that has been published that binds in this domain [25]. CP-640186 (2) has been shown to be an inhibitor of rat liver ACC1 and rat skeletal muscle ACC2 with IC50's of 53 and 63 nM, respectively [26]. CP-640186 also inhibited fatty acid synthesis in HepG2 cells (IC50 = 1.8 mM). Oral dosing of CP-640186 to Sprague-Dawley rats lowered malonyl-CoA levels in liver (ED50 55 mg/kg), heart (ED50 8 mg/ kg), soleus (ED50 6 mg/kg), and quadriceps (ED50 15 mg/kg). Rats dosed orally with 100 mg/kg of CP-640186 also showed an 89% reduction in RQ without increased consumption of O2, indicating a shift in metabolic preference from carbohydrates to lipids. CP-640186 has been cocrystal-lized with the CT domain of yeast ACC [27].

More recently, a series of alkynyl thiazoles was reported, of which some analogs exemplified by 3 (ACC2 IC50 = 38 nM, ACC1 IC50 > 30,000 nM) showed high selectivity for ACC2 versus ACC1 [28]. Sprague-Dawley rats dosed orally with 3 showed a dose-dependent reduction of malonyl-CoA in liver and muscle, indicating that inhibition of ACC2 alone may be sufficient to achieve a metabolic response. Extensive structure-activity relationship (SAR) studies around the phenyl and acetylene groups in this series have also been reported [29-31]. Additionally, gene expression analysis in animals treated with 3 suggested that the peroxisome proliferator-activated receptor a (PPARa) pathway was upregulated by ACC2 inhibition [32]. Although other compounds from the same group did not show PPARa activity, such an effect of 3 could potentially confound the interpretation of the pharmacology of its ACC inhibition.

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