S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice.


BACKGROUND AND PURPOSE:Small molecule glucokinase activators (GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile. EXPERIMENTAL APPROACH:Activity of the compounds was assessed in vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events. KEY RESULTS:S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time. CONCLUSIONS AND IMPLICATIONS:In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.


Br J Pharmacol


De Ceuninck F,Kargar C,Charton Y,Goldstein S,Perron-Sierra F,Ilic C,Caliez A,Rolin JO,Sadlo M,Harley E,Vinson C,Ktorza A




Has Abstract


2013-07-01 00:00:00












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    abstract::Bovine culture endothelial cells (BAECs) generate platelet-activating factor (Paf) following activation by bradykinin (Bk 0.1 nM), the ionophore, A23187 (3 microM), and ATP (10 microM), but Paf is not released from the cells. These stimuli also elicit generation of prostacyclin (PGI2). The specific and competitive Paf...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Stewart AG,Dubbin PN,Harris T,Dusting GJ

    更新日期:1989-03-01 00:00:00

  • NCX 2057, a novel NO-releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models.

    abstract:BACKGROUND AND PURPOSE:We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)-releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro-inflammatory mediators through NO-mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and...

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    authors: Ronchetti D,Borghi V,Gaitan G,Herrero JF,Impagnatiello F

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  • Synergistic inhibition by BQ-123 and BQ-788 of endothelin-1-induced contractions of the rabbit pulmonary artery.

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    authors: Fukuroda T,Ozaki S,Ihara M,Ishikawa K,Yano M,Nishikibe M

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  • Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris.

    abstract:BACKGROUND AND PURPOSE:Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ i...

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    journal_title:British journal of pharmacology

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    authors: Sims C,Harvey RD

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  • NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Dijk SN,Francis PT,Stratmann GC,Bowen DM

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  • Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes.

    abstract:BACKGROUND AND PURPOSE:3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepati...

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    authors: Min C,Zheng M,Zhang X,Caron MG,Kim KM

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    authors: Redrobe JP,Calo G,Guerrini R,Regoli D,Quirion R

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  • Effect of verapamil on the pulmonary vasoconstrictor action of prostaglandin F2 alpha and a synthetic PGH2 analogue.

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    authors: Angerio AD,Fitzpatrick TM,Kot PA,Ramwell PW,Rose JC

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  • Th1-type immune responses to Porphyromonas gingivalis antigens exacerbate angiotensin II-dependent hypertension and vascular dysfunction.

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    journal_title:British journal of pharmacology

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    journal_title:British journal of pharmacology

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    authors: Schwanstecher C,Dickel C,Ebers I,Lins S,Zünkler BJ,Panten U

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  • 5-Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea-pig isolated detrusor muscle.

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    authors: Gulati OD,Patel DG

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    authors: Vonend O,Grote T,Oberhauser V,Von Kügelgen I,Rump LC

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    authors: Richard V,Ghaleh B,Berdeaux A,Giudicelli JF

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    authors: Becker C,Porzig H

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    authors: Adcock JJ,Garland LG

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    authors: Triggle CR

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Guimaraes S,Nunes JP

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    journal_title:British journal of pharmacology

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    authors: Butchers PR,Fullarton JR,Skidmore IF,Thompson LE,Vardey CJ,Wheeldon A

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