Aminomethylpyrimidines as novel DPP-IV inhibitors: A 105-fold activity increase by optimization of aromatic substituents

Peters, Jens‐Uwe; Weber, Silja; Kritter, Stéphane; Weiß, Peter; Wallier, Angelina; Boehringer, Markus; Hennig, Michael; Kuhn, Bernd; Loeffler, Bernd-Michael

doi:10.1016/j.bmcl.2004.01.019

Cited by 76 publications

(47 citation statements)

References 25 publications

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“…The conformational space of the docked compounds was explored using OMEGA software. The software settings that best reproduced the co-crystallized poses of several ligand-DPP IV complexes (2G5T, 2G63, 1RWQ, 2AJL, 1X70, and 2HHA) [73,88,[92][93][94] were employed in the docking experiment.…”

Section: Docking Experimentsmentioning

confidence: 99%

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

2008

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Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.

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Section: Docking Experimentsmentioning

confidence: 99%

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

2008

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“…We reproduced successfully the experimental poses of known inhibitors (RMSD \1.5 Å ) with DPP IV crystal structures available from the PDB (Bernstein et al, 1977;Berman et al, 2003) using GOLD (Jones et al, 1997;Hartshorn et al, 2007, Thoma et al, 2003Peters et al, 2004). Binding modes of pyrrolidine nitriles NVP-DPP728 (Hughes et al, 1999), and FE999011 (Sudre et al, 2002), reversible covalent DPP IV inhibitors, were satisfactorily predicted without applying covalent bond constraint.…”

Section: In-vitro Inhibition Of Dpp IV Activity and Enzyme Kinetic Exmentioning

confidence: 83%

“…For substrate recognition, the substrate must enter the hydrophobic pocket S1, close to Ser630, and interact with glutamates Glu205 and/or Glu206 (Glu-Glu motif), that was shown to be essential for enzymatic activity (Abbott et al, 1999). Interactions of ligands with side chains constituting the spacious S2 pocket, especially ones with hydrophobic, long or bulky side chains, generally showed an enhanced binding (Brandt, 2000;Peters et al, 2004).…”

Section: In-vitro Inhibition Of Dpp IV Activity and Enzyme Kinetic Exmentioning

confidence: 99%

“…The first two of such drugs, the incretin mimetic Exenatide Ò (Byetta-Amylin Pharmaceuticals) and the DPP IV inhibitor Sitagliptin Ò (JanuviaMerck & Co.) (Kesty et al, 2008), were approved by the FDA in 2005 and 2006, respectively. Reported inhibitors of DPP IV have various heterocyclic structures and include pyrrolidines (Hughes et al, 1999), piperazines (Brockunier et al, 2004), amino-substituted pyrimidines (Peters et al, 2004), etc. We propose 6-imino-2-thioxo-2,5-dihydro-4(3H)-pyrimidinones as a promising scaffold for design of new DPP IV competitive inhibitors, which differs from the other published ones.…”

Section: Introductionmentioning

confidence: 99%

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6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors

et al. 2010

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Dipeptidyl peptidase IV is a glycoprotein which removes N-terminal dipeptides from physiologically relevant polypeptides. An homologous series of 6-imino-2-thioxo-5-{[3,4,5-tris(methyloxy)phenyl]methyl}-2,5-dihydro-4(3H)-pyrimidinones has been tested for inhibition of DPP IV activity. The inhibitory effects at 0.1 mM were observed. Enzyme kinetic studies revealed that compounds inhibit DPP IV activity competitively. According to the molecular docking analysis, the inhibitors are anchored into the DPP IV hydrolytic site by interactions of the pyrimidinone core with Glu206, Tyr662, and Tyr547, with the alkyl chain entering the S1 pocket. We conclude that pyrimidinone-like compounds are a promising new scaffold for reversible inhibition of DPP IV.

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“…Small molecule inhibitors of DP-IV have been reported in the literatures and progressed into clinical trials with positive results. [8][9][10][11][12][13][14] In a previous paper, 15,16) we have described the synthesis and biological evaluation of a new series of pyrazolidine derivatives (Fig. 1).…”

mentioning

confidence: 99%

Pyrazolidine Derivatives with Heteroaryl Urea as Dipeptidyl Peptidase IV Inhibitors

et al. 2005

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Aminomethylpyrimidines as novel DPP-IV inhibitors: A 105-fold activity increase by optimization of aromatic substituents

Cited by 76 publications

References 25 publications

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors

Pyrazolidine Derivatives with Heteroaryl Urea as Dipeptidyl Peptidase IV Inhibitors

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