Discovery of a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Qin, Jun; Rao, Ashwin U.; Chen, Xiao; Zhu, Xiaohong; Liu, Zhidan; Huang, Xianhai; Degrado, Sylvia J.; Huang, Ying; Xiao, Dong; Aslanian, Robert; Cheewatrakoolpong, Boonlert; Zhang, Hongtao; Greenfeder, Scott; Farley, Constance; Cook, John A.; Kurowski, Stan; Li, Qiu; Heek, Margaret van; Chintala, Madhu; Wang, Ganfeng; Hsieh, Yunsheng; Li, Fangbiao; Palani, Anandan

doi:10.1021/ml100251u

Cited by 22 publications

(13 citation statements)

References 32 publications

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“…Schering-Plough (now Merck) developed a potent GPR109A agonist, SCH900271 [ 73 ]. In rats, SCH900271 suppressed plasma FFA 70 % and TG 49 % 1 h post-dose with a longer duration of TG suppression (8 h) compared with niacin (<6 h).…”

Section: Niacin Receptor Mimeticsmentioning

confidence: 99%

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Goel

Dunbar

2016

Curr Atheroscler Rep

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Two cardiovascular outcome trials established niacin 3 g daily prevents hard cardiac events. However, as detailed in part I of this series, an extended-release (ER) alternative at only 2 g nightly demonstrated no comparable benefits in two outcome trials, implying the alternative is not equivalent to the established cardioprotective regimen. Since statins leave a significant treatment gap, this presents a major opportunity for developers. Importantly, the established regimen is cardioprotective, so the pathway is likely beneficial. Moreover, though effective, the established cardioprotective regimen is cumbersome, limiting clinical use. At the same time, the ER alternative has been thoroughly discredited as a viable substitute for the established cardioprotective regimen. Therefore, by exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective variations facing little meaningful competition from their predecessors. Thus, shrewd developers could effectively tap into a gold mine at the grave of the ER alternative. The GPR109A receptor was discovered a decade ago, leading to a large body of evidence commending the niacin pathway to a lower cardiovascular risk beyond statins. While mediating niacin’s most prominent adverse effects, GPR109A also seems to mediate anti-lipolytic, anti-inflammatory, and anti-atherogenic effects of niacin. Several developers are investing heavily in novel strategies to exploit niacin’s therapeutic pathways. These include selective GPR109A receptor agonists, niacin prodrugs, and a niacin metabolite, with encouraging early phase human data. In part II of this review, we summarize the accumulated results of these early phase studies of emerging niacin mimetics.

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Section: Niacin Receptor Mimeticsmentioning

confidence: 99%

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Goel

Dunbar

2016

Curr Atheroscler Rep

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“…24−27 Our lead identification strategy, which involved an extensive structure− activity relationship (SAR) investigation of the C-2 region of a thiobarbituric acid core, had been shown to activate the receptor and has been reported previously. 28 Further screening and elaboration of both the C-2 and the C-5 regions provided a pyranopyrimidinedione series suitable for optimization as NAR agonists. A comparison of the in vitro activity data of the compounds synthesized is shown in Table 1.…”

mentioning

confidence: 99%

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Palani

Chen

et al. 2011

ACS Med. Chem. Lett.

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Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.

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“…The (±)-α-hydroxy stearic acid 3 is prepared in two steps from stearic acid 1 by bromination [ 24 ] using Hell-Volhard-Zelinsky condition giving compound 2 followed by hydrolysis in 88% overall yield (Scheme 2 ). The (±)-β-Hydroxy stearic acid 8 is synthesized by the procedure described by Masamune [ 25 , 26 ], which involves homologation of palmitic acid 5 [ 27 ] using in situ generated magnesium monomethylmalonate to a preformed acyl imidazole to produce the β-keto stearic acid methyl ester, which is reduced [ 28 ] with sodium borohydride in ethanol providing 7 . Saponification with 1 N NaOH resulted in the formation of (±)-β-hydroxy stearic acid 8 in 77% overall yield (Scheme 3 ).…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization

et al. 2014

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BackgroundFatty acid vesicles are an important part of protocell models currently studied. As protocells can be considered as pre-biological precursors of cells, the models try to contribute to a better understanding of the (cellular) origin of life and emphasize on 2 major aspects: compartmentalization and replication. It has been demonstrated that lipid-based membranes are amenable to growth and division (shell replication). Furthermore compartmentalization creates a unique micro-environment in which biomolecules can accumulate and reactions can occur. Pioneering research by Sugawara, Deamer, Luisi, Szostak and Rasmussen gave more insight in obtaining autocatalytic, self-replicating vesicles capable of containing and reproducing nucleic acid sequences (core replication). Linking both core and shell replication is a challenging feat requiring thorough understanding of membrane dynamics and (auto)catalytic systems. A possible solution may lie in a class of compounds called nucleolipids, who combine a nucleoside, nucleotide or nucleobase with a lipophilic moiety. Early contributions by the group of Yanagawa mentions the prebiotic significance (as a primitive helical template) arising from the supramolecular organization of these compounds. Further contributions, exploring the supramolecular scope regarding phospoliponucleosides (e.g. 5’-dioleylphosphatidyl derivatives of adenosine, uridine and cytidine) can be accounted to Baglioni, Luisi and Berti. This emerging field of amphiphiles is being investigated for surface behavior, supramolecular assembly and even drug ability.ResultsA series of α/β-hydroxy fatty acids and α-amino fatty acids, covalently bound to nucleoside-5′-monophosphates via a hydroxyl or amino group on the fatty acid was examined for spontaneous self-assembly in spherical aggregates and their stability towards intramolecular cleavage. Staining the resulting hydrophobic aggregates with BODIPY-dyes followed by fluorescent microscopy gave several distinct images of vesicles varying from small, isolated spheres to higher order aggregates and large, multimicrometer sized particles. Other observations include rod-like vesicle precursors. NMR was used to assess the stability of a representative sample of nucleolipids. 1D 31P NMR revealed that β-hydroxy fatty acids containing nucleotides were pH-stable while the α-analogs are acid labile. Degradation products identified by [1H-31P] heteroTOCSY revealed that phosphoesters are cleaved between sugar and phosphate, while phosphoramidates are also cleaved at the lipid-phosphate bond. For the latter compounds, the ratio between both degradation pathways is influenced by the nucleobase moiety. However no oligomerization of nucleotides was observed; nor the formation of 3′-5′-cyclic nucleotides, possible intermediates for oligonucleotide synthesis.ConclusionsThe nucleolipids with a deoxyribose sugar moiety form small or large vesicles, rod-like structures, vesicle aggregates or large vesicles. Some of these aggregates can be considered as intermediate forms in ve...

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Discovery of a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Cited by 22 publications

References 32 publications

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization

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