Structure–activity-relationship of amide and sulfonamide analogs of omarigliptin

Chen, Ping; Feng, Danqing; Qian, Xiaoxia; Apgar, James M.; Wilkening, Robert R.; Kuethe, Jeffrey T.; Gao, Ying‐Duo; Scapin, Giovanna; Cox, Jason M.; Doss, George A.; Eiermann, George J.; He, Huaibing; Li, Xiaohua; Lyons, Kathryn A.; Metzger, Joseph M.; Petrov, A. N.; Wu, Joseph K.; Xu, Shiyao; Weber, Ann E.; Yan, Yong-Bin; Roy, Ranabir Sinha; Biftu, Tesfaye

doi:10.1016/j.bmcl.2015.10.070

Cited by 16 publications

(10 citation statements)

References 23 publications

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“…Nitrogen-containing heterocycles are ubiquitous in pharmaceuticals, agrochemicals, and natural products. , Often, saturated heterocycles provide particularly advantageous properties. − Specifically, substituted tetrahydro-pyrrolo-pyrazole heterocycles are known to be biologically active with a variety of potential applications (Figure ). − A direct and efficient synthesis of these functionally dense heterocycles from simple starting materials would be empowering. , Classically, tetrahydro-pyrrolo-pyrazole heterocycles are generated through cycloaddition of a diazo species with activated maleimide derivatives. , More recently, Zard demonstrated that hydrazones with pendant alkenes can be oxidized to the corresponding diazo species, which subsequently undergoes an intramolecular cycloaddition (Scheme a) . Jahn demonstrated that a domino aza -Michael reaction can afford similar heterocycles using n -BuLi and NfN 3 . , …”

Section: Introductionmentioning

confidence: 99%

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A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles

2020

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Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom.Over 30 examples are provided with an average isolated yield of 71% (ranging from 40% to 94%). The reaction was easily scaled to use more than one gram of starting material, and the products can be readily diversified.

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Section: Introductionmentioning

confidence: 99%

“…HRMS (ESI-TOF): m/z [M + Na] + calcd for C 13 H 16 N 4 NaO 2 + , 283.1165; found, 283.1149. ((3aS,6aS)-3-(2-Nitrophenyl)-3a,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6a(1H)-yl)methanol(11). To a solution of compound 5b (48.6 mg, 0.168 mmol) in MeOH (2 mL) was added NaBH 4(28.4…”

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confidence: 99%

A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles

2020

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“…Virtual screening (VS) has been used over recent years to discover DPP‐IV inhibitors in molecular databases, with most of the inhibitors identified having bioactivity in the μM range (see Table , but with no measurement of their selectivity over related enzymes like DPP8 and DPP9 (inhibition of either DPP8 or DPP9 has been suggested as responsible for alopecia, thrombocytopenia, reticulocytopenia, multiorgan histopathological changes, enlarged spleen, and mortality in rats and gastrointestinal toxicity in dogs, while DPP9 inhibition produces neonatal lethality in mice) . In contrast, several recent structure–activity studies (SAR) in the literature describe the synthesis of novel and selective compounds with nM activity as DPP‐IV inhibitors …”

Section: Introductionmentioning

confidence: 99%

“…60,61 In contrast, several recent structure-activity studies (SAR) in the literature describe the synthesis of novel and selective compounds with nM activity as DPP-IV inhibitors. 45,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] In the last decade, many reviews focusing on DPP-IV inhibitors have been published. 81-91 Some of these address a wide range of topics such as the incretin system and incretin mimetics, 85 DPP-IV inhibitor selectivity and the implications of DPP-IV inhibition, 84 and even structure optimization in the search for chemical stability, selectivity, and favorable pharmacokinetic properties.…”

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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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“…Omarigliptin (MK-3102; Figure 1) is a novel long-acting DPP-4 inhibitor, which supported once-weekly dosing for treatment of T2DM (Biftu et al, 2014). It was approved in Japan in 2015 and the phase III clinical trial had been completed (Chen et al, 2015a). Compared to once-daily DPP-4 inhibitor (sitagliptin, linagliptin, vildagliptin, saxagliptin and alogliptin), omarigliptin is more potent to inhibit DPP-4…”

Section: Introductionmentioning

confidence: 99%

Ultra‐high pressure liquid chromatography–tandem mass spectrometry method for the determination of omarigliptin in rat plasma and its application to a pharmacokinetic study in rats

2017

Biomedical Chromatography

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Omarigliptin is a novel long-acting dipeptidyl peptidase-4 inhibitor used for the treatment of type 2 diabetes. In this work, a sensitive and selective ultra-high pressure liquid chromatography tandem mass spectrometry method was developed and validated for the determination of omarigliptin in rat plasma. Sample preparation was performed by protein precipitation with acetonitrile. Chromatographic separation of analytes was achieved on an RRHD Eclipse Plus C18 column (2.1 × 50 mm, 1.8 μm), using gradient mobile phase (0.1% formic acid-acetonitrile) at a flow rate of 0.4 mL/min. Detection was performed in multiple reaction monitoring mode, with target fragment ions m/z 399.1 → 152.9 for omarigliptin and m/z 237.1 → 194 for the internal standard. The total run time was 4 min. Retention time of omarigliptin and internal standard was 1.25 and 2.12 min, respectively. Relative standard deviation (%) of the intra- and inter-day precision was below 10.0%, and accuracy was between 97.9% and 105.3%. Calibration curve was established over the range 2-5000 ng/mL with good linearity. The lower limit of quantification and limit of detection of omarigliptin were 2 and 0.25 ng/mL, respectively. Mean recoveries were in the range 87.3-95.1% for omarigliptin. No matrix effect was observed in this method. This novel method has been successfully applied to a pharmacokinetic study of omarigliptin in rats. The absolute bioavailability of omarigliptin was identified as high as 87.31%.

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Structure–activity-relationship of amide and sulfonamide analogs of omarigliptin

Cited by 16 publications

References 23 publications

A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles

A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles

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

Ultra‐high pressure liquid chromatography–tandem mass spectrometry method for the determination of omarigliptin in rat plasma and its application to a pharmacokinetic study in rats

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