Synthesis of spiro[chroman-2,4′-piperidin]-4-one derivatives as acetyl-CoA carboxylase inhibitors

Shinde, Pundlik; Srivastava, Sanjay; Odedara, Rajendra; Tuli, Davinder; Munshi, Siralee; Patel, Jitendra; Zambad, S. P.; Sonawane, Rajesh; Gupta, Ramesh C.; Chauthaiwale, Vijay; Dutt, Chaitanya

doi:10.1016/j.bmcl.2008.11.099

Cited by 34 publications

(18 citation statements)

References 8 publications

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“…Such a specific and potent inhibitors of BuChE may have a potential for use in the treatment of dementias such as Alzheimer's disease [67,68]. The spiro[chroman-2-4 0 -piperidine]carbonyl derivatives 50 were tested as acetyl-CoA carboxylase inhibitors showing 16e64% inhibition at 10 mM concentration, being, however, less active than appropriate phenoxazines [69].…”

Section: Other Activitiesmentioning

confidence: 99%

Recent progress in biological activities of synthesized phenothiazines

Pluta¹,

Morak‐Młodawska²,

Jeleń³

2011

European Journal of Medicinal Chemistry

264

122

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Section: Other Activitiesmentioning

confidence: 99%

Recent progress in biological activities of synthesized phenothiazines

Pluta¹,

Morak‐Młodawska²,

Jeleń³

2011

European Journal of Medicinal Chemistry

264

122

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“…Because human ACC1 and ACC2 produce two separate pools of malonyl-CoA with dramatically different functions, isozyme-specific inhibitors are highly desirable. The current arsenal of small-molecule inhibitors of mammalian ACC includes several classes of compounds with different chemical cores and submicromolar IC 50 and, in some cases, a modest isozyme specificity (22)(23)(24)(25)(26)(27). No drugs targeting human ACC have yet been developed, based on these compounds or others.…”

Section: Fatty Acid Metabolism | Human Healthmentioning

confidence: 99%

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

Marjanovic

Chalupská

Patenode

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC 50 and having no effect on human ACC1 at 100 μM.fatty acid metabolism | human health

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“…The binding modes of these compounds are highly different from each other, suggesting that there are many different molecular mechanisms for inhibiting this catalytic activity. A large number of potent and chemically diverse inhibitors of mammalian ACCs have been reported recently (23)(24)(25)(26)(27)(28)(29). It will be very interesting to characterize whether any of these compounds also function at the CT active site.…”

Section: Molecular Basis For Distinct Sensitivity To Resistance Mutatmentioning

confidence: 99%

A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim

Xiang

Callaghan

Watson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and are attractive targets for drug discovery. Haloxyfop and tepraloxydim belong to two distinct classes of commercial herbicides and kill sensitive plants by inhibiting the carboxyltransferase (CT) activity of ACC. Our earlier structural studies showed that haloxyfop is bound near the active site of the CT domain, at the interface of its dimer, and a large conformational change in the dimer interface is required for haloxyfop binding. We report here the crystal structure at 2.3 Å resolution of the CT domain of yeast ACC in complex with tepraloxydim. The compound has a different mechanism of inhibiting the CT activity compared to haloxyfop, as well as the mammalian ACC inhibitor CP-640186. Tepraloxydim probes a different region of the dimer interface and requires only small but important conformational changes in the enzyme, in contrast to haloxyfop. The binding mode of tepraloxydim explains the structure-activity relationship of these inhibitors, and provides a molecular basis for their distinct sensitivity to some of the resistance mutations, as compared to haloxyfop. Despite the chemical diversity between haloxyfop and tepraloxydim, the compounds do share two binding interactions to the enzyme, which may be important anchoring points for the development of ACC inhibitors.diabetes ͉ fatty acid metabolism ͉ herbicides ͉ structure-based drug design A cetyl-CoA carboxylases (ACCs) catalyze the production of malonyl-CoA from acetyl-CoA and CO 2 in two steps (1-3). The biotin carboxylase (BC) activity catalyzes the ATPdependent carboxylation of a biotin cofactor, and then the carboxyltransferase (CT) activity catalyzes the transfer of this activated carboxyl group to the acceptor acetyl-CoA. In bacteria, the BC and CT activities reside in separate subunits of the ACC holoenzyme. In comparison, ACCs are large, multidomain enzymes in most eukaryotes, with highly conserved BC and CT domains.ACCs are crucial enzymes for the metabolism of fatty acids. Two isoforms of ACCs are present in mammals, and mice lacking ACC2 have elevated fatty acid oxidation and reduced body fat and body weight (4). ACCs are attractive targets for the discovery of anti-diabetes and anti-obesity agents (5, 6), and currently there is significant interest in understanding their catalysis, regulation, and mechanism of inhibition.The relevance of ACCs for drug discovery is also underscored by the fact that two distinct classes of compounds, as illustrated by haloxyfop (FOPs) and tepraloxydim (DIMs) (Fig. 1A), are potent inhibitors of ACCs from sensitive plants and are in wide use as herbicides (7-12). These compounds inhibit the CT activity, as does a potent inhibitor of mammalian ACCs, CP-640186 (13), suggesting that the CT domain may be a suitable target for discovering small-molecule inhibitors against ACCs.We have reported the crystal structures of the CT domain of yeast ACC and its complex with CoA (14), haloxyfop (15), and CP-640186 (16). In comparison, the human CT domain has been ...

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Synthesis of spiro[chroman-2,4′-piperidin]-4-one derivatives as acetyl-CoA carboxylase inhibitors

Cited by 34 publications

References 8 publications

Recent progress in biological activities of synthesized phenothiazines

Recent progress in biological activities of synthesized phenothiazines

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim

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