Discovery and Structure−Activity Relationships of Piperidinone- and Piperidine-Constrained Phenethylamines as Novel, Potent, and Selective Dipeptidyl Peptidase IV Inhibitors

Pei, Zhonghua; Li, Xiaofeng; Geldern, Thomas W von; Longenecker, K.L.; Pireh, Daisy; Stewart, Kent D.; Backes, Bradley J.; Lai, Chunqiu; Lübben, Thomas; Ballaron, Stephen J.; Beno, David W. A.; Kempf-Grote, Anita J; Sham, Hing L.; Trevillyan, James M.

doi:10.1021/jm061436d

Cited by 87 publications

(60 citation statements)

References 25 publications

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“…[1][2][3][4][5][6] Consequently, a sizable portion of recent US patents reports on organic process development of aromatic heterocycles. [7,8] A useful synthetic tool for the modification of such compounds is the SuzukiMiyaura coupling, [9,10] which has been applied for the preparation of arylpyridines, [11,12] bipyridines, [11][12][13][14][15] arylpyrimidines, [16][17][18] pyridopyridines [11,12,[19][20][21] and aryltriazines, [22,23] the synthesis of nucleosides [24,25] or the introduction of thiophene, [26,27] benzothiazole [28] or indolyl [29][30][31][32] moieties. Nonetheless, the cross-coupling chemistry of heterocyclic substrates suffers from limitations.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

121

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A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

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Section: Introductionmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

121

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“…The death toll and economic costs associated with diabetes and its complications are enormously high. 1 The incretin hormone glucagon-like peptide 1 (GLP-1) has been the subject of intense research efforts related to the treatment of type 2 diabetes. 2 Secreted from the L cells of the small intestine, 3 GLP-1 stimulates glucose-induced insulin secretion, inhibits glucagon secretion, 4 and delays the gastric emptying, all of which are beneficial in controlling the blood glucose.…”

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confidence: 99%

“…Such increase was also seen when the lactam of compound 18a was introduced to an ethyl or a 2-ethoxy-2-oxoethyl, while isopropylation of 18a slightly decreased inhibitory activity. The benzo[e] [1,4]diazepine-2-one derivatives 10 (represented as example 18i) were synthesized starting from 1-(bromomethyl)-4,5-difluoro-2-nitrobenzene (11i), which was converted to compound 12i via replacement reaction with glycine methyl ester, and the later was protected by benzyl chloroformate to furnish 13i. Compound 13i was then reduced to give 14i, which was converted to 15i via hydrolysis and subsequent intramolecular cyclization.…”

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confidence: 99%

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

Jiang

Zhou

Chen

et al. 2015

ACS Med. Chem. Lett.

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Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.

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“…Under similar conditions the reaction with arylsulfenyl chlorides of amides containing bulky substituents at the nitrogen atom resulted in 5-arylsulfanyl-6-phenyltetrahydropyran-2-iminium perchlorates, which by treatment with aqueous ethanol were converted into the corresponding derivatives of pyran-2-ones.Piperidin-2-ones are compounds with unique biological characteristics [1][2][3]. They underlie the preparation of piperidine systems included into the composition of many alkaloids and physiologically active substances [4][5][6].…”

mentioning

confidence: 99%

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

et al. 2011

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Sterically nonhindered N-alkyl(aryl)amides of cinnamylacetic acid in the reaction with phenyl(4-tolyl)sulfenyl chlorides in acetic acid in the presence of lithium perchlorate undergo a selective cyclization into 5-arylsulfanyl-6-phenylpiperidin-2-ones. Under similar conditions the reaction with arylsulfenyl chlorides of amides containing bulky substituents at the nitrogen atom resulted in 5-arylsulfanyl-6-phenyltetrahydropyran-2-iminium perchlorates, which by treatment with aqueous ethanol were converted into the corresponding derivatives of pyran-2-ones.Piperidin-2-ones are compounds with unique biological characteristics [1][2][3]. They underlie the preparation of piperidine systems included into the composition of many alkaloids and physiologically active substances [4][5][6]. Therefore nowadays new substituted piperidones are synthesized [7][8][9][10][11].The introduction of sulfanyl groups in the piperidone ring can essentially modify the chemical and biological characteristics. In particular, among the sulfanyl derivatives of piperidin-2-oneов (δ-lactams) compounds were found capable to inhibit the activation of p38MAP-kinase [12], a very important quality both for prophylactic and treatment of infl ammation and autoimmune diseases, rheumatoid arthritis, infectious diseases, atherosclerosis, and pancreatitis.Although there are well developed approaches to nonfunctional piperidones, the methods of the synthesis of 5-alkyl(aryl)sulfanyl-substituted piperidones [12][13][14] are multistage and apply diffi cultly accessible and toxic reagents.Considering the synthetic potential of the reaction of electrophilic cyclization of unsaturated amides [15] and aiming at the development of the synthesis of 5-arylsulfanylpiperidin-2-ones we examined in detail the arylsulfenylation of cinnamylacetamides Iа-Ig. These compounds react with arylsulfenyl chlorides IIа-IIc at room temperature in acetic acid in the presence of an equimolar amount of LiClO 4 as "dopping-additive" [16,17] forming cyclization products whose structure is controlled mainly by the steric parameters of the substituent at the nitrogen atom of the nucleophilic substrate and the electronic characteristics of the electrophilic reagent.Amide with sterically nonhindered aliphatic (Ib, Ic) or aromatic (If, Ig) substituents react with phenyl-or 4-tolylsulfenyl chlorides (IIа, IIb) giving 5-arylsulfanyl-6-phenylpiperidones IIIb-IIIg, IIIi, IIIj (path а) in 81-95% yield (Scheme 1). In event of 4-nitrophenylsulfenyl chloride a decreased selectivity of reaction is observed due to the nucleophilic involvement of the oxygen atom of the iniial amides (path b), and as a result forms a mixture of compounds III and IV in the ratio 5 : 1 from amide If and 4 : 1 from amide Ig.In the reaction of unsubstituted amide Ia with 4-tolylsulfenyl chloride (IIb) lactam IIIa was isolated.

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Discovery and Structure−Activity Relationships of Piperidinone- and Piperidine-Constrained Phenethylamines as Novel, Potent, and Selective Dipeptidyl Peptidase IV Inhibitors

Cited by 87 publications

References 25 publications

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

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