Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure

Griffith, David A.; Dow, Robert L.; Huard, Kim; Edmonds, David J.; Bagley, Scott W.; Polívková, Jana; Zeng, Dongxiang; García-Irizarry, Carmen N.; Southers, James A.; Esler, William P.; Amor, Paul A.; Loomis, Kathrine; McPherson, Kirk; Bahnck, Kevin B.; Préville, Cathy; Banks, Tereece; Moore, Dianna E.; Mathiowetz, Alan M.; Menhaji‐Klotz, Elnaz; Smith, Aaron; Doran, Shawn D.; Beebe, David A.; Dunn, Matthew F.

doi:10.1021/jm401033t

Cited by 41 publications

(22 citation statements)

References 18 publications

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“…Insulin acts directly via hepatic insulin signaling to stimulate net hepatic glycogen synthesis and hepatic DNL, but insulin's extrahepatic action to suppress lipolysis in WAT is critical for maintaining normal carbohydrate and lipid metabolism by inhibiting hepatic gluconeogenesis and curtailing hepatic esterification of fatty acids to triglyceride. (126)(127)(128). Proof-of-concept studies in rodent models of NALFD and T2D demonstrate that mildly increasing hepatic mitochondrial inefficiency can safely reverse hypertriglyceridemia, ectopic lipid-induced (DAG/nPKC) liver and muscle insulin resistance, steatohepatitis, liver fibrosis, and diabetes, offering a novel therapeutic target for T2D and nonalcoholic steatohepatitis (NASH) (81,118,129).…”

Section: Discussionmentioning

confidence: 99%

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,010

819

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In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

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Section: Discussionmentioning

confidence: 99%

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,010

819

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“…Compound 452 showed excellent oral bioavailability, moderate systemic clearance, and acceptable exposure in rat pharmacokinetic studies. The oral dosing of rats with 452 resulted in potent, dose-proportional inhibition of ACC activity as measured by incorporation of 14 C in DNL product [ 349 ].…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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“…The first potent and selective small molecule dual ACC1/2 inhibitor, CP-640186, was reported in 2003 40 . Pharmacologic ACC inhibition was shown to inhibit formation of malonyl-CoA, stimulate fatty acid oxidation and block DNL both in vitro and in vivo 40, 41, 42, 43, 44, 45. This compound was the starting point for optimization that ultimately led to the discovery of PF-05175157, 44 a systemically distributed, CNS excluded, dual ACC1/2 inhibitor, which was progressed into clinical development in 2010 (NCT01274663).…”

Section: Regulators Of Hepatic Lipid Metabolismmentioning

confidence: 99%