Substituted piperazines as novel dipeptidyl peptidase IV inhibitors

Brockunier, Linda; He, Jiafang; Colwell, Lawrence F.; Habulihaz, Bahanu; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Marsilio, Frank; Patel, Reshma A.; Teffera, Yohannes; Wu, Joseph K.; Thornberry, Nancy A.; Weber, Ann E.; Parmee, Emma R.

doi:10.1016/j.bmcl.2004.06.065

Cited by 98 publications

(72 citation statements)

References 6 publications

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“…Piperazine and its derivatives have been intensively investigated owing to their interesting pharmacological, cardiovascular and autonomic properties (Conrado et al, 2008). Piperazine derivatives are found in biologically active compounds across a number of different therapeutic areas such as antifungal, antibacterial, antimalarial, antipsychotic, antidepressant and antitumour activity against colon, prostate, breast, lung and leukemia tumors (Brockunier et al, 2004;Bogatcheva et al, 2006;Essid et al, 2013). In the present work, we report the preparation and the crystal structure of an organic proton transfer salt (C 5 H 14 N 2 ) 2+ ·2(HC 2 O 4 ) -, (I).…”

Section: Methodsmentioning

confidence: 99%

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1-Methylpiperazine-1,4-dium bis(hydrogen oxalate)

Essid¹,

Marouani²,

Rzaigui³

2014

Acta Cryst E

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Key indicators: single-crystal X-ray study; T = 293 K; mean (C-C) = 0.002 Å; R factor = 0.052; wR factor = 0.162; data-to-parameter ratio = 32.9.In the crystal structure of the title compound,, the two crystallographically independent hydrogen oxalate anions are linked by strong intermolecular O-HÁ Á ÁO hydrogen bonds, forming two independent corrugated chains parallel to the b axis. These chains are further connected by N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds originating from the organic cations, forming a three-dimensional network. The diprotonated piperazine ring adopts a chair conformation, with the methyl group occupying an equatorial position.

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Section: Methodsmentioning

confidence: 99%

“…For the biological activity of piperazines, see: Conrado et al (2008); Brockunier et al (2004); Bogatcheva et al (2006). For related structures, see: Essid et al (2013); Dutkiewicz et al (2011);Vaidhyanathan et al (2002); Ejsmont & Zaleski (2006).…”

Section: Related Literaturementioning

confidence: 99%

1-Methylpiperazine-1,4-dium bis(hydrogen oxalate)

Essid¹,

Marouani²,

Rzaigui³

2014

Acta Cryst E

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“…[5] Additionally,r eactions cale-up in as hort timeframe is an important consideration, especially with hit-to-lead optimizations in medicinal chemistry. [6][7][8][9][10] With these considerations in mind, we have developed as ingle-phase flow chemistry approach for rapid amide synthesis, with scalability addressed at the outset of the research. The centerpiece of this strategy involves the use of at hin film vortex fluidic device (VFD).…”

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confidence: 99%

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine

Britton

Chalker

Raston

2015

Chemistry A European J

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Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.

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“…The consensus score was calculated by summing the three binned scores and the best-ranked positions had the consensus score 3. Consensus scoring was done with seven known inhibitors within the scored compound set: Ile-Pro-Ile (Thoma et al, 2003), NVP-DPP728 (Hughes et al, 1999), FE999011 (Sudre et al, 2002), (S)-isoleucine thiazolidide P32/98 (Sorbera et al, 2001), cyclohexylglycine pyrrolidide, aminomethylpyrimidine representative (Peters et al, 2004), and substituted piperazine representative (Brockunier et al, 2004).…”

Section: Experimental Protocolsmentioning

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%

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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Substituted piperazines as novel dipeptidyl peptidase IV inhibitors

Cited by 98 publications

References 6 publications

1-Methylpiperazine-1,4-dium bis(hydrogen oxalate)

1-Methylpiperazine-1,4-dium bis(hydrogen oxalate)

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine

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

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