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Li C.-J.,Nanchang University | Le Z.-P.,Nanchang University | Zhao C.-S.,Shanghai Sun Sail Pharmaceutical Science and Technology Co.
Chinese Journal of New Drugs

Objective: To synthesize derivatives of DPP-IV inhibitor alogliptin and study their hypoglycemic activities.Methods: The strategy of skeleton transition was used to transform pyrimidinedione skeleton into fused heterocyclic structures pyrrolo[1,2-f][1,2,4]triazine, then eight new compounds were designed and synthesized through structural optimization, and their structures were determined by 1H-NMR and LC-MS. The hypoglycemic activities of all these compounds were studied through pharmacodynamic experiments in vitro and in vivo.Results: Compare with the control drug alogliptin (IC50=8.47 nmol·L-1), the DPP-4 inhibitory activities in vitro of the new compounds were relatively better except compounds 12a and 12d (IC50>9 nmol·L-1), and the activities of compounds 12e, 12f, 12g, and 12h (IC50<4 nmol·L-1) were 2 to 3.5 times of that of alogliptin. Compound 12h showed a better pharmacokinetic profile in the pharmacological experiments in vivo, and had better hypoglycemic effect than alogliptin in the oral glucose tolerance test.Conclusion: Compound 12h has good hypoglycemic activity, and is suitable for further preclinical experiments. Source

Yang X.-L.,Nanchang University | Wang T.-C.,Shanghai Sun Sail Pharmaceutical Science and Technology Co. | Lin S.,Nanchang University | Fan H.-X.,Shanghai Sun Sail Pharmaceutical Science and Technology Co.
Chinese Journal of New Drugs

Objective: To explore the antitumor drugs with a new structure and better activity. Methods: 2-Aminobenzoic acid was used as raw material; then the triazole intermediates was synthesized by iodine generation reaction, cyclization, chlorination, nucleophilic reaction, Sonogashira coupling, deprotection and combined with azides; finally, 18 target compounds were generated via Suzuki coupling. Their structures were confirmed by 1H-NMR and LC-MS. The in vitro anti-proliferative activity in SKBR3 and A549 cells was assessed by MTT detection assay. Results and Conclusion: The inhibiting activities of most compounds were stronger than lapatinib in A549 cells. The inhibitory activity of compound 7 was higher than the marketed drug lapatinib in both cell lines; its pharmakinetic properties were excellent in mice; it was effective in A549 cells. The compound may compensate the inadequacy of lapatinib in the treatment of non-small cell lung cancer. Source

Yang X.L.,Nanchang University | Wang T.C.,Shanghai Sun Sail Pharmaceutical Science and Technology Co. | Lin S.,Nanchang University | Fan H.X.,Shanghai Sun Sail Pharmaceutical Science and Technology Co.
Archiv der Pharmazie

Overexpression of epidermal growth factor receptor (EGFR) tyrosine kinases has been found in a variety of cancers such as breast, ovarian, colon, and non-small-cell lung cancers, which is associated with poor prognosis in patients. In an effort to find effective irreversible inhibitors of the EGFR tyrosine kinase family (mainly HER2), two series of HER2 tyrosine kinase inhibitors with thieno[3,2-d]pyridine and thieno[2,3-d]pyridine as central part and with a basic α,β-unsaturated amide side chain were developed. The α,β-unsaturated amide side chain (the Michael acceptor) at the 6-position, which forms a covalent bond to Cys773 located in the ATP binding pocket of the EGFR enzyme, is a major factor in the generation of irreversible inhibition. In our study, thienopyrimidine instead of quinazoline was used as the central structure, and different substituents were introduced at the 4-position to investigate the structure-activity relationships. The thieno[2,3-d]pyrimidine derivatives 16a-d showed potent HER2 enzyme inhibition and anti-proliferative activity against SK-BR-3 cells. Especially, (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)thieno[2,3-d] pyrimidin-6-yl)-4-(dimethylamino)but-2-enamide 16d was identified as a potential irreversible HER2 inhibitor. Both its catalytic enzyme activity profile and its cellular efficacy were found to be superior to those of the marketed drug lapatinib. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Shan Z.,Shandong University of Traditional Chinese Medicine | Peng M.,Hunan University | Fan H.,Shanghai Sun Sail Pharmaceutical Science and Technology Co. | Lu Q.,Shandong University of Traditional Chinese Medicine | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters

A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC50 <50 nM) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes. © 2010 Elsevier Ltd. All rights reserved. Source

Zhu Y.,East China University of Science and Technology | Xia S.,East China University of Science and Technology | Zhu M.,Shanghai Sun Sail Pharmaceutical Science and Technology Co. | Yi W.,Shanghai Sun Sail Pharmaceutical Science and Technology Co. | And 4 more authors.
European Journal of Medicinal Chemistry

A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)- hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan- 2-amine fumaric acid (17h, IC50 = 78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h. © 2010 Elsevier Masson SAS. All rights reserved. Source

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