Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors

Park, Woul Seong; Kang, Seung Kyu; Jun, Mi Ae; Shin, Mi Sik; Kim, Ki Young; Rhee, Sang Dal; Bae, Myung Ae; Kim, Min Sun; Kim, Kwang-Rok; Kang, Nam Sook; Yoo, Sung‐Eun; Lee, Jie‐Oh; Song, Dong Hyun; Silinski, Peter; Schneider, Stephen E.; Ahn, Jin Hee; Kim, Sung Soo

doi:10.1016/j.bmcl.2011.01.041

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…19,20,35 The carbonyl group in aminoacyl moiety forms a hydrogen bond with Tyr547. 16,19,20 Biftu et al replaced the β-aminobutanoyl moiety with a cyclohexylamine analog. The nitrogen of cyclohexylamine forms hydrogen bonds with Glu205, Glu206, and Tyr662 as well.…”

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

“…Among β-aminoacyl thiazolidines with an amino acid moiety, valine derivative shows in vitro and in vivo potency in rat and dog models. 16 Arg125 is significant in the coordination of the P2 residue's carbonyl group. A negative environment near Arg125 gives an electrostatic intermolecular interaction which results in an increased affinity for DPP-4.…”

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

“…Unsubstituted diazepanone shows lower DPP-4 inhibitory potential, while aryl-alkyl diazepanone substituents give potent DPP-4 inhibitors, but with poor oral bioavailability. 19 ■ DPP-4 INHIBITORS WITH PYRIMIDINE-2,4-DIONE OR ANALOGS AS P1′ FRAGMENT Many pyrimidine-2,4-dione derivatives/analogs as DPP-4 inhibitors have been reported 23−28 (Figure 9), among which alogliptin (16), trelagliptin (17), and linagliptin (18) (Figure 10) are approved DPP-4 inhibitors with pyrimidine-2,4-dione or analogs as the P1′ fragment. 31,36,37 Approved DPP-4 inhibitors with pyrimidine-2,4-dione or analogs as P1′ fragment interact with the S1′ and/or S2′ pockets of the enzyme besides the S1 and S2 domains.…”

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

“…Hydrogen bonds are created between the backbone NH of Tyr631 and carbonyl oxygen of pyrimidine-2,4-dione. 36,37 The cyanobenzyl group at the N1 position of pyrimidine-2,4-dione (16,17) effectively fills the S1 domain, and the nitrile group forms a hydrogen bond with Arg125. The amino group of aminopiperidine moiety at the C6 position of pyrimidine-2,4-dione creates a salt bridge to Glu205 and Glu206.…”

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

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Structure–Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase-4 Inhibitors

2021

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Approved and potent reported dipeptidyl peptidase-4 (DPP-4) inhibitors with gliptin-like structures are classified here according to their structures and mechanisms of the inhibition in three groups: (i) those with pyrrolidine or analogs as P1 fragment with α-aminoacyl linker, (ii) structures with trifluorophenyl moiety or analogs as P1 fragment with β-aminobutanoyl linker, and (iii) DPP-4 inhibitors with pyrimidine-2,4-dione or analogs as P1′ fragment. The structure−activity relationship analysis was performed for those whose cocrystallized structures with the enzyme were published. While inhibitors with pyrrolidine and trifluorophenyl moiety or analogs as P1 fragment bind in a similar way in S1, S2 and S2 extensive domains of the enzyme, the binding mode of pyrimidine-2,4-dione derivatives/analogs differs with additional interactions in S1′ and S2′ pockets. Three general schemes of fragmented gliptins and gliptin-like structures with the enzyme and protein−ligand interaction fingerprints were made, which might be useful in the creation of DPP-4 inhibitor's design strategies.

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Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

Section: ■ Dpp-4 Inhibitors With Pyrrolidine or Analogs As P1 Fragmen...mentioning

confidence: 99%

See 2 more Smart Citations

Structure–Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase-4 Inhibitors

2021

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“…This compound showed excellent selectivity toward DPP4 inhibition with an IC 50 value of 1 nM in vitro compared with another DDP isozyme, sitagliptin, which has an IC 50 value of 20 nM. KR-66223 is chemically and metabolically stable, and showed no CYP inhibition, hERG binding, or cytotoxicity [10,11].…”

Section: Introductionmentioning

confidence: 98%

Determination of a dipeptidyl peptidase IV agonist, β-aminoacyl containing thiazolidine derivatives (KR-66223) in rat plasma by liquid chromatography–tandem mass spectrometry

Kim

Park

Jang

et al. 2011

Journal of Pharmaceutical and Biomedical Analysis

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Synthesis of Diheteroatomic Five‐Membered Heterocyclic Compounds from α,β‐Unsaturated Aldehydes

Keiko

Вчисло

2016

Asian J Org Chem

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The recent increasei ni nterest in the chemistry of azoles has been owing to their paramount importance in several essential fields of research, such as pharmacology, medicine, biology, the organic synthesis of fine chemicals, agriculturalc hemistry, and the chemical industry.T his Focus Review summarizes and highlights recently developed methods for the synthesis of five-membered N,N-, N,O-, andN ,Sheterocycles based on the transformations of 2-alkenals. Over the last 15 years, these reactions, which often differ from reactions involving other a,b-unsaturatedc arbonyl compoundsi nt erms of methoda nd results, have gathered significant momentum. The multitude of catalytic and tech-nological novelties discussed in this Focus Review,s uch as asymmetricm etal-and organocatalysis,o ne-pot multicomponent reactions that proceed through domino, cascade, or tandem sequences, and microwave activation,p romote the formation of ad iverse range of target products, the structures of which becomec lear from the mechanistic schemes given in this Focus Review.T he mechanisms discussed reflect great advances in the chemo-, regio-, and stereoselectivity of the reactions of 2-alkenals, which allows new azoles and related compounds (imidazoles, pyrazoles, oxazoles, thiazoles, and their hydrogenatedd erivatives) to be synthesized.[a] Prof.The ORCID identification number(s) for the author(s) of this articlecan be found under http://dx.Scheme2.One-potsynthesis of imidazoles 8 and tentativemechanism of the reaction.T s= 4-toluenesulfonyl, TMS = tert-butyltrimethylsilyl, Bn = benzyl, Lg = leaving group.Scheme3.Enantioselective synthesiso f3-hydroxyalkyl and 3-aminoalkyli midazo[1,2-a]pyridines (9)through an asymmetricorganocatalytic [3+ +2] annulation strategy.Alk = alkyl.Scheme4.One-potsynthesis of imidazole-containingc ondensed heterocycles by the reaction of 2-alkoxypropenalswith N-binucleophiles.Scheme9.Aroute to 2-(1'-alkoxyvinyl)imidazolidines 27 through the condensation of alkoxy propenals.

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Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors

Cited by 13 publications

References 28 publications

Structure–Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase-4 Inhibitors

Structure–Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase-4 Inhibitors

Determination of a dipeptidyl peptidase IV agonist, β-aminoacyl containing thiazolidine derivatives (KR-66223) in rat plasma by liquid chromatography–tandem mass spectrometry

Synthesis of Diheteroatomic Five‐Membered Heterocyclic Compounds from α,β‐Unsaturated Aldehydes

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