Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors

Nitta, Akira; Fujii, H.; Sakami, Satoshi; Satoh, Mikiya; Nakaki, Junko; Satoh, Shiho; Kumagai, Hiroki; Kawai, Hideki

doi:10.1016/j.bmcl.2012.09.099

Cited by 21 publications

(9 citation statements)

References 40 publications

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“…The physical characteristics, IR, 1 H NMR, 13 C NMR, and elemental analysis data for all intermediates and target compounds were reported in this study 6, 7-Dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (29) To a solution of 2-(3, 4-dimethoxyphenyl) ethanamine (9.05 g, 50 mmol) in EtOH (30 mL), paraformaldehyde (1.8 g) was added. The mixture was stirred for 2 h at room temperature and treated with 6 N hydrochloric acid to adjust the mixture to pH = 3.…”

Section: Appendixmentioning

confidence: 99%

“…A group of 38 different compounds, which were collected from different references, were divided into a training set ( Figure 3) and test set ( Figure S1; 18,[23][24][25][26][27][28][29][30][31][32]. All the compounds were selected according to the following rules: (i) both training and test sets should cover the widest possible range of molecular bioactivities (IC 50 ); (ii) both the low-active and high-active compounds should be included; (iii) both training and test sets should cover diverse structures.…”

Section: Data Collectionmentioning

confidence: 99%

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Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation

Xing

Zhang

et al. 2014

Chem Biol Drug Des

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Inhibition of dipeptidyl peptidase IV is an important approach for the treatment of type-2 diabetes. In this study, we reported a multistage virtual screening workflow that integrated 3D pharmacophore models, structural consensus docking, and molecular mechanics/generalized Born surface area binding energy calculation to identify novel dipeptidyl peptidase IV inhibitors. After screening our in-house database, two hit compounds, HWL-405 and HWL-892, having persistent high performance in all stages of virtual screening were identified. These two hit compounds together with several analogs were synthesized and evaluated for in vitro inhibition of dipeptidyl peptidase IV. The experimental data indicated that most designed compounds exhibited significant dipeptidyl peptidase IV inhibitory activity. Among them, compounds 35f displayed the greatest potency against dipeptidyl peptidase IV in vitro with the IC50 value of 78 nm. In an oral glucose tolerance test in normal male Kunming mice, compound 35f reduced blood glucose excursion in a dose-dependent manner.

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Section: Appendixmentioning

confidence: 99%

Section: Data Collectionmentioning

confidence: 99%

Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation

Xing

Zhang

et al. 2014

Chem Biol Drug Des

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“…Nitta et al reported the DPP-IV inhibitory activity of 3-amino-N-substituted-4-(substituted phenyl) butanamides in two communications [11,12] calculated as concentration required to inhibit 50 % (IC 50 ) of DPP-IV derived from human colonic carcinoma cells (Caco-2). After removing two duplicates (17,28) from the series, a dataset of 48 molecules was used in the present work (Table 1, fig.…”

Section: Biological Activity Datamentioning

confidence: 99%

Structural Requirements for some 3-amino-N-substituted-4-(substituted phenyl) Butanamides as Dipeptidyl Peptidase-IV Inhibitors Using 3D-QSAR and Molecular Docking Approaches

Ghode¹,

Jain²

2017

pharmaceutical-sciences

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Ghode and Jain: QSAR and Docking Study of Butanamide DerivativesDipeptidyl peptidase-IV is well thought out as one of the key targets for treatment of type 2 diabetes mellitus and diverse scaffolds have proven effective in designing novel dipeptidyl peptidase-IV inhibitors. To this end, three dimensional quantitative structure activity relationship analysis and molecular docking studies were performed on a set of 3-amino-N-substituted-4-(substituted phenyl) butanamides to explore the structural requirements for dipeptidyl peptidase-IV inhibitory activity using k-nearest neighbour molecular field analysis and AutoDock Vina, respectively. The compounds were arbitrarily assigned to active, moderately active and less active classes according to their biological activities. The most significant k-nearest neighbour model exhibited internal cross validation coefficient (q , concordance correlation coefficient and mean absolute error provided further confidence in the predictability of both the models. Apropos the docking results, the compounds from active, moderately active and less active classes exhibited different binding patterns. Whereas the active compounds such as 12x and 12v occupied a similar space in the active site cavity as the crystallographic ligand, sitagliptin (PDBID:1X70); the binding modes of compounds from moderately active and inactive classes were distinct from the latter. The findings of this study can provide an impetus for design of prospective potent dipeptidyl peptidase-IV inhibitorss.

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“…Similarly, the tetrahydrothiopyran moiety is a common structural framework present in a number of bioactive compounds and promising pharmaceuticals such as antihypertensive agents (e.g., compound 9 ), anti‐Alzheimer's disease agents (e.g., compound 10 ), antidiabetes agents (e.g., compounds 11 and 14 ), antimicrobial agents (e.g., compound 12 ) and antimitotic agents (e.g., compound 13 ; Scheme ). Moreover, the tetrahydrothiopyrans can also be transformed into a variety of valuable structures .…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Asymmetric Synthesis of Tetrahydrothiophenes and Tetrahydrothiopyrans

2017

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Tetrahydrothiophenes and tetrahydrothiopyrans are an important class of compounds both from synthetic and biological points of view and have attracted the attention of many synthetic chemists and biologists over the years. Their high synthetic utility and diverse distribution in nature have made tetrahydrothiophenes and tetrahydrothiopyrans privileged motifs in organic chemistry. The last decade has witnessed great exploration of organocatalytic domino methods for the synthesis of enantiopure tetrahydrothiophenes and tetrahydrothiopyrans containing multiple stereocentres. The application of new bidentate reagents containing sulfur moieties in the development of double Michael reactions has revolutionized their synthesis. This microreview highlights recent organocatalytic asymmetric approaches to the synthesis of tetrahydrothiophenes and tetrahydrothiopyrans and describes the advances that have been made over the years.

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Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors

Cited by 21 publications

References 40 publications

Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation

Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation

Structural Requirements for some 3-amino-N-substituted-4-(substituted phenyl) Butanamides as Dipeptidyl Peptidase-IV Inhibitors Using 3D-QSAR and Molecular Docking Approaches

Organocatalytic Asymmetric Synthesis of Tetrahydrothiophenes and Tetrahydrothiopyrans

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