Aminomethylpyrimidines as Novel DPP‐IV Inhibitors: A 10<sup>5</sup>‐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:10.1002/chin.200429145

Cited by 4 publications

(6 citation statements)

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“…Currently, the Protein Structure Database (PDB) provides about 20 DP4 crystal structures including apo‐proteins,17, 31, 32 cocrystallized small molecules,7, 17, 18, 33–37 short peptides,32, 38 and protein–protein interaction domains 38. The protein naturally occurs as a dimer and also crystallizes in a dimeric arrangement.…”

Section: Methodsmentioning

confidence: 99%

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Mazzoleni¹,

Bisogno

Garaventa

et al. 2005

Cancer

102

109

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BACKGROUNDAlthough > 90% of children with nonmetastatic rhabdomyosarcoma (RMS) achieve complete remission with current treatment, up to one‐third of them experience a recurrence. Survival rates are not always poor in patients who develop recurrences; thus, prognostic factors are needed to tailor salvage treatment.METHODSThe current analysis included 125 children who were affected by localized RMS and were enrolled in 3 consecutive Italian protocols (RMS79, RMS88, and RMS96) who developed recurrences after complete remission. Patient, tumor, and treatment characteristics were studied in univariate and multivariate analyses to determine the independent significance of different factors.RESULTSThe median time from diagnosis to recurrence was 17.8 months. Most patients had local recurrences (72%). The 5‐year overall survival (OS) rate was 28.3% ± 8.7%. Multivariate analysis identified 4 factors that were associated with poor survival: 1) alveolar subtype (relative risk [RR], 2.0), 2) parameningeal or “other” sites (RR, 2.6), 3) systemic recurrence (RR, 3.1), and 4) recurrence on therapy (RR, 2.3). The absence of any of these risk factors identified a “favorable risk” group (12% of patients) with a 5‐year OS rate of 71.8% ± 23.5%. Patients with a single risk factor (32%) had an OS rate of 37.5% ± 17.2%. Combining patients with 0 or 1 risk factor, the OS rate was 66.5% in the subgroup who had not received radiotherapy compared with an OS rate of 30.3% in the subgroup who had received radiotherapy; this difference was significant (P = 0.03).CONCLUSIONSThe results of the current analysis demonstrated that groups with a different prognosis can be identified among patients with recurrent RMS. Patients with a nonalveolar histology, a primary site other than the parameningeal or “other” sites, local recurrence, and recurrence off therapy had a better prognosis. First‐line treatment may have an impact on prognostic variables. In fact, patients who had no or only one risk factor and patients who had tumors with a nonalveolar histology benefited more from salvage therapy if they had not received radiotherapy for their initial treatment. These data may be useful in planning risk‐adapted salvage protocols. Cancer 2005;. © 2005 American Cancer Society.

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Section: Methodsmentioning

confidence: 99%

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Mazzoleni¹,

Bisogno

Garaventa

et al. 2005

Cancer

102

109

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“…Initially the database was filtered so as to remove those molecules that are either reactive or show poor ADME properties. The remaining molecules (together with some approved DPP‐IV drugs used to validate the VS protocol) were then docked with Glide to 1RWQ by using a grid containing two docking constraints (one hydrophobic constraint at the S 1 pocket and one hydrophilic constraint close to the Glu dyad). During this docking, three consecutive steps were performed (the first with Glide‐HTVS, the second with GlideSP and the third with GlideXP) and the sample for each step was the top 10% according to the results of the previous scoring function (i.e., around 18,000 molecules for Glide‐HTVS, 1800 for GlideSP, and 180 for GlideXP).…”

Section: Reviewing Virtual Screening For Dpp‐iv Inhibitorsmentioning

confidence: 99%

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

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“…This is illustrated by the aminopyrimidines 17, for which the location of the 2,4-dichloro-phenyl ring in the S1 pocket is depicted in Fig. (5b) [21]. Table (1) shows the SAR for small substitutions around this phenyl ring.…”

Section: S1 Pocketmentioning

confidence: 98%

“…A considerably larger gain in binding affinity compared to the pyrrolidines could be achieved by small substituents on aromatic rings in the S1 pocket [21,36,37]. This is illustrated by the aminopyrimidines 17, for which the location of the 2,4-dichloro-phenyl ring in the S1 pocket is depicted in Fig.…”

Section: S1 Pocketmentioning

confidence: 99%

“…As can be seen from Fig. (2), the number of structures deposited to the Protein Data Bank (PDB) [17] has increased steadily since then, most of them have been solved as protein-inhibitor complexes [9,[18][19][20][21][22][23][24]. The abundance of publicly available DPP-IV X-ray information provides a good basis to analyze the molecular recognition processes in this enzyme.…”

Section: Introductionmentioning

confidence: 97%

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Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

Kuhn

Hennig²,

Mattei

2007

CTMC

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The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the X-ray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.

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Aminomethylpyrimidines as Novel DPP‐IV Inhibitors: A 10⁵‐Fold Activity Increase by Optimization of Aromatic Substituents.

Cited by 4 publications

References 1 publication

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

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Aminomethylpyrimidines as Novel DPP‐IV Inhibitors: A 105‐Fold Activity Increase by Optimization of Aromatic Substituents.

Cited by 4 publications

References 1 publication

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

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Product

Resources

About

Aminomethylpyrimidines as Novel DPP‐IV Inhibitors: A 10⁵‐Fold Activity Increase by Optimization of Aromatic Substituents.