Abstract
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
MeSH terms
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Acetyl-CoA Carboxylase / antagonists & inhibitors*
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Drug Design
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indoles / chemical synthesis*
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Indoles / chemistry
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Isoenzymes / antagonists & inhibitors
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Liver / enzymology
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Muscle, Skeletal / enzymology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Quantitative Structure-Activity Relationship
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Rats
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
Substances
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2'-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2'H-spiro(piperidine-4,5'-pyrano(3,2-c)pyrazol)-7'(6'H)-one
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Benzimidazoles
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Hypoglycemic Agents
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Indazoles
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Indoles
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Isoenzymes
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Pyrazoles
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Spiro Compounds
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Acetyl-CoA Carboxylase