Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes

Brigance, Robert; Meng, Wei; Fura, Aberra; Harrity, Thomas; Wang, Aiying; Zahler, Robert; Kirby, Mark; Hamann, Lawrence G.

doi:10.1016/j.bmcl.2010.06.063

Cited by 49 publications

(28 citation statements)

References 19 publications

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“…Therefore, we performed additional experiments in acetic acid at 90°C with varied reaction times, reagent ratios, and strong acids as catalysts. Under the studied conditions, variations in the reaction time (entry 7) and the 5a:6a molar ratio (entries 8,9) did not increase the yield. In the presence of a 40% aqueous solution of HBr, only a trace yield of the desired product was detected by NMR in the resulting precipitate due to the low solubility of the hydrobromide of the starting aminoheterocycle in the reaction mixture (entry 10).…”

Section: ■ Introductionmentioning

confidence: 89%

“…Since the 1960s, Trapidil, which is a coronary vasodilator, has been used in medicine, 1a and most recently, a new drug to treat hepatitis C (Filibuvir) passed stage II clinical trials. 1c Compounds containing the [1,2,4]triazolo [1,5-a]pyrimidine core exhibit biological activity in a variety of therapeutic domains (i.e., anticancer, 3 antimalarial 4a and anti-Leishmania, 4b,c antibacterial, 5 antiviral, 6 including anti-HIV 6d,e and anti-HCV, 1c,6f antiinflammatory, 7 hypoglycemic, 8 microtubule-stabilizing CNS, 9 hypnotic, 10 and other types of activities 11 ).…”

Section: ■ Introductionmentioning

confidence: 99%

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Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones

et al. 2015

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The acid-catalyzed condensation between 2-aminosubstituted [1,2,4]triazolo[1,5-a]pyrimidines and their analogues with various saturation of the pyrimidine ring and 1,3-diketones or 1,1,3,3-tetramethoxypropane was evaluated as a new approach for the synthesis of diversely substituted polycyclic derivatives of triazolopyrimidine. The reaction of 4,5,6,7-tetrahydro- or aromatic aminotriazolopyrimidines results in selective formation of the corresponding [1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium salts, and the condensation of substrates containing the 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine fragment is accompanied by a cascade rearrangement with unusual recyclization of the dihydropyrimidine ring to yield partially hydrogenated [1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium or pyrimido[1',2':1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium salts. The proposed methodology exhibits a wide scope, providing rapid access to polycondensed derivatives of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. DFT calculations of the Gibbs free energies of possible isomers were performed to rationalize the experimentally observed reactivity and selectivity.

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Section: ■ Introductionmentioning

confidence: 89%

Section: ■ Introductionmentioning

confidence: 99%

Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones

et al. 2015

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“…The organic layer was evaporated to the dryness under reduced pressure and resultant intermediates (2-7) were obtained in excellent yields. Step III: General procedure for synthesis of compounds (8)(9)(10)(11)(12)(13) To a solution of 2-amino-4-methyl-4H-thiazolo [4, 5-d] pyrimidine-5,7-dione (0.25 mmol) in dry DMF (1 ml), added anhydrous potassium carbonate (0.75 mmol) and mixture was heated initially at 70°C for 2 h under continuous stirring. At 70°C drop wise added the solution of N-substituted chloracetamide derivative (0.25 mmol) in dry DMF to the reaction mixture.…”

Section: Methodsmentioning

confidence: 99%

“…The synthesized thiazolopyrimidine derivatives (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were evaluated in-vitro for DPP IV enzyme inhibitory activity and results obtained are reported as micromolar inhibitory concentration, IC 50 (lM). The DPP IV inhibition was determined using human DPP IV, and the inhibitory activity was obtained for various substitutions around thiazolopyrimidine scaffold.…”

Section: In-vitro Dpp IV Activitymentioning

confidence: 99%

“…Insertion of an acetamide linker produced potent inhibitors, which might have allowed conformational changes and may be responsible for increase in inhibitory effect ( Table 1). The alkyl chlorides having ethylene and methylene linker (14-18) caused considerably lower potency than N-substituted chloracetamide (8)(9)(10)(11)(12)(13) derivatives. N-substituted chloracetamide derivatives (2-7) which were synthesized from secondary amines and chloroacetyl chloride, have been explored due to their substrate specificity for DPP IV inhibition (20).…”

Section: In-vitro Dpp IV Activitymentioning

confidence: 99%

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Synthesis, Evaluation and Molecular Docking of Thiazolopyrimidine Derivatives as Dipeptidyl Peptidase IV Inhibitors

et al. 2012

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A series of thiazolopyrimidine derivatives was designed, synthesized and screened for in‐vitro inhibition of Dipeptidyl Peptidase IV (DPP IV). The SAR study indicated the influence of substituted chemical modifications on thiazolopyrimidine scaffold. Compound 9 (IC50 = 0.489 μm) and 10 (IC50 = 0.329 μm) having heterocyclic‐substituted piperazine with acetamide linker resulted as most potent DPP IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of both the compounds 9 and 10 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin induced diabetic rat model. Molecular docking studies illustrated the probable binding mode and interactions of thiazolopyrimidine nucleus and its derivatives at binding site of receptor. The binding site for DPP IV is composed of active site region (catalytic triad of Ser630, Asp708 and His740) including S1 and S2 sub‐pocket. The aryl moiety of compounds 9, 10 and 11 were observed to occupy S2 binding pocket and interacted with aromatic ring of Tyr662 and Tyr666 acquired through π‐π interaction. Thus, it is indicated that occupancy of the highly hydrophobic S2 pocket is more important for DPP IV inhibitory activity. The present study on substituted thiazolopyrimidine derivatives shows good to moderate inhibitory potential of DPP IV enzyme.

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Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1‐c][1,2,4]‐triazines and Pyrazolo[5,1‐c][1,2,4]triazines as Potential Antidiabetic Agents

Русинов

Сапожникова

Bliznik

et al. 2017

Archiv der Pharmazie

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Inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme activity and prevention of advanced glycation end (AGE) products formation represents a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In the frames of this research study, several triazolo- and pyrazolotriazines were synthesized and evaluated as inhibitors of AGE products formation, DPP4, glycogen phosphorylase and α-glucosidase activities, as well as AGE cross-link breakers. From the two considered classes of heterocyclic compounds, the pyrazolotriazines showed the highest potency as antiglycating agents and DPP4 inhibitors. Structure-activity relationships (SAR) for these compounds, which can be considered as potential drugs for the treatment of type 2 diabetes, were evaluated.

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Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes

Cited by 49 publications

References 19 publications

Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones

Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones

Synthesis, Evaluation and Molecular Docking of Thiazolopyrimidine Derivatives as Dipeptidyl Peptidase IV Inhibitors

Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1‐c][1,2,4]‐triazines and Pyrazolo[5,1‐c][1,2,4]triazines as Potential Antidiabetic Agents

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