Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

Larsen, Scott D.; Poel, Toni J.; Filipski, Kevin J.; Kohrt, Jeffrey T.; Pfefferkorn, Jeffrey A.; Sorenson, Roderick J.; Tait, Bradley D.; Askew, Valerie; Dillon, Lisa; Hanselman, Jeffrey C.; Lu, Gina H.; Robertson, Andrew W.; Sekerke, Catherine; Kowala, Mark C.; Auerbach, Bruce J.

doi:10.1016/j.bmcl.2007.08.004

Cited by 14 publications

(11 citation statements)

References 28 publications

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“…There is evidence that the likelihood of statin-induced myalgia can be reduced by targeting HMG-CoA reductase inhibitors to hepatic tissues and limiting peripheral exposure, and it has been demonstrated that the hepatoselectivity of a given HMG-CoA reductase inhibitor is related to its degree of lipophilicity. [10][11][12][13] In general, lipophilic statins tend to achieve higher levels of exposure in nonhepatic peripheral tissues, whereas more hydrophilic statins tend to be more hepatoselective. 9,14 To meet the challenge of finding novel HMG-CoA reductase inhibitors with improved efficacy and tolerability, we undertook a discovery effort to identify a novel series of inhibitors with best-in-class preclinical efficacy and hepatoselectivity.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

Sarver¹,

Bills²,

Bolton³

et al. 2008

J. Med. Chem.

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Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

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Section: Introductionmentioning

confidence: 99%

Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

Sarver¹,

Bills²,

Bolton³

et al. 2008

J. Med. Chem.

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“…Based on a route previously developed by our medicinal chemistry colleagues toward a related oxypyrazole series, we were able to readily synthesize hydroxypyrazole 24b as a key intermediate for the second generation synthesis of 1 (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor

Bowles

Boyles

Choi

et al. 2010

Org. Process Res. Dev.

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Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.

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“…Quinoline derivatives analogous to pitavastatin (e.g., derivative 10) have also been identified as interesting targets in this context [25,32,36]. In addition, drug candidates based on other heterocyclic motifs that had previously been less frequent in statin chemistry, such as pyrazole (e.g., derivatives 11, 12, 13) [24,26,31,34] and imidazole (e.g., derivatives 14, 15) [29,33], have also been prepared and investigated within this framework (Fig. 3).…”

Section: Hepatoselective Super-statinsmentioning

confidence: 98%

Recent Progress in the Synthesis of Super-Statins

Časar

2015

Topics in Heterocyclic Chemistry

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Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateralchain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.

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Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

Cited by 14 publications

References 28 publications

Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor

Recent Progress in the Synthesis of Super-Statins

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