Discovery of a Biaryl Cyclohexene Carboxylic Acid (MK-6892): A Potent and Selective High Affinity Niacin Receptor Full Agonist with Reduced Flushing Profiles in Animals as a Preclinical Candidate

Shen, Hong C.; Ding, Fa‐Xiang; Raghavan, Subharekha; Deng, Qiaolin; Luell, Silvi; Forrest, Michael J.; Carballo-Jane, Ester; Wilsie, Larissa; Krsmanovic, Mihajlo L.; Taggart, Andrew K.P.; Wu, Kenneth K.; Wu, Tsuei-Ju; Cheng, Kang; Ren, Ning; Cai, Tian-Quan; Chen, Qing; Wang, Junying; Wolff, Michael; Tong, Xinchun; Holt, Tom G.; Waters, M. Gerard; Hammond, Milton L.; Tata, James R.; Colletti, Steven L.

doi:10.1021/jm100022r

Cited by 49 publications

(43 citation statements)

References 17 publications

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“…6g), which resulted in a preclinical candidate from the Merck anthranilic acid effort. It was also found (Ding et al, 2010;Schmidt et al, 2010) that the cyclohexene ring system in such compounds can be further substituted (e.g., Fig. 6h).…”

Section: Receptor Classification With Pharmacological Toolsmentioning

confidence: 69%

“…The authors concluded that the tetrahydro variants of anthranilic acid derivatives might fare better than the parent molecules because they seemed to yield improved oral bioavailability and better cytochrome P450 profiles. A recent publication (Shen et al, 2010) describes the discovery of MK-6892 (Fig. 6g), which resulted in a preclinical candidate from the Merck anthranilic acid effort.…”

Section: Receptor Classification With Pharmacological Toolsmentioning

confidence: 99%

See 1 more Smart Citation

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Offermanns¹,

Colletti²,

Lovenberg³

et al. 2011

Pharmacological Reviews

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160

117

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Section: Receptor Classification With Pharmacological Toolsmentioning

confidence: 69%

Section: Receptor Classification With Pharmacological Toolsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Offermanns¹,

Colletti²,

Lovenberg³

et al. 2011

Pharmacological Reviews

Self Cite

160

117

View full text Add to dashboard Cite

“…This supports the hypothesis that a G protein-biased ligand would maintain beneficial effects on plasma lipids in the absence of β-arrestin-mediated flushing. Interestingly, GPR109A agonists have been identified that exhibit antilipolytic actions with significantly reduced cutaneous flushing [74–78]. Some of these compounds also show reduced receptor internalization and extracellular signal-regulated kinase (ERK) activation [74], which could result from non-engagement of β-arrestin.…”

Section: β-Arrestin-mediated Signalingmentioning

confidence: 99%

Therapeutic potential of β-arrestin- and G protein-biased agonists

Whalen

Rajagopal

Lefkowitz

2011

Trends in Molecular Medicine

475

454

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Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that β-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and β-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states.

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“…In clinical studies, NicA reduced carotid atherosclerosis (Lee et al, 2009) and improved nitric oxide (NO)-dependent vasodilation in the brachial artery (Thoenes et al, 2007;Warnholtz et al, 2009). Improvement of endothelial function by NicA cannot be explained by the activation of GPRs, because they are not present on the surface of endothelial cells and specific GPR agonists such as hydroxy-2-pyridinyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyl-1-oxopropyl]amino]-1-cyclohexene-1-carboxylic acid) do not display direct vasoprotective properties (Shen et al, 2010). Moreover, in vitro studies on endothelial cell cultures have demonstrated the ability of NicA to reduce the expression of adhesion molecules (Ganji et al, 2009(Ganji et al, , 2014Stach et al, 2012) and to diminish the release of tumor necrosis factor-a (TNFa) (Ganji et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

Mateuszuk

Jasztal

Maślak

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/ low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/ LDLR 2/2 mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F 1a and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B 2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR 2/2 mice, an effect associated with an improvement in prostacyclin-and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA.

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Discovery of a Biaryl Cyclohexene Carboxylic Acid (MK-6892): A Potent and Selective High Affinity Niacin Receptor Full Agonist with Reduced Flushing Profiles in Animals as a Preclinical Candidate

Cited by 49 publications

References 17 publications

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Therapeutic potential of β-arrestin- and G protein-biased agonists

Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low-Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid

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