Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

The anti-hyperuricemic effects of compound CC18022 targeting xanthine oxidase / 药学学报

Hyperuricemia is not only the biochemical basis of gout, but also closely related to the development of metabolic syndrome, cardiovascular diseases, chronic kidney disease, etc. Xanthine oxidase (XOD) is the key catalytic enzyme for uric acid biosynthesis, therefore the vital target for anti-hyperuricemic drugs. In this study, compound CC18022 was designed and synthesized specifically targeting to XOD. Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD. In the in vitro study, CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration (IC50) value in the order of nmol·L-1, which is relative to the XOD inhibitor febuxostat. By using both acute and chronic hyperuricemic mice model, compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo. The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In the acute hyperuricemic mice, CC18022 significantly inhibited serum XOD activity, and also the XOD activity in intestine and liver, which were related to purine absorption and metabolism. Therefore, the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects, making it a favorable candidate for further research.

Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1) / 药学学报

Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC50 value of 0.061 μmol·L-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.

Design, synthesis and biological evaluation of amide derivatives as xanthine oxidase inhibitors / 药学学报

Xanthine oxidase (XO) is a key enzyme in the synthesis of uric acid. Therefore, XO inhibitors play an important role in the antihyperuricemic therapy. Based on the template structures of febuxostat and topiroxostat, 18 amide derivatives were designed and synthesized. Among them, six showed apparent inhibitory activity against XO under the concentration of 10 μmol·L-1. Molecular docking revealed the possible interaction mode of this compound class, which may provide a clue for further molecular design.

Design, synthesis and biological evaluation of oxadiazole derivatives as xanthine oxidase inhibitors / 药学学报

Xanthine oxidase (XO) is an important target for the treatment of hyperuricemia and gout. Based on the two known non-purine xanthine oxidase inhibitors, febuxostat and topiroxostat, 14 oxadiazole derivatives have been designed and synthesized. These compounds have been evaluated against XO and five of them exhibited significant inhibitory activities at the concentrations below 10 μmol·L-1.

SAR of benzoyl sulfathiazole derivatives as PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. We have previously identified the benzoyl sulfathiazole derivative II as a non-competitive PTP1B inhibitor with in vivo insulin sensitizing effects. Preliminary SAR study on this compound series has been carried out herein, and thirteen new compounds have been designed and synthesized. Among them, compound 10 exhibited potent inhibition against human recombinant PTP1B with the IC50 value of 3.97 micromol x L(-1), and is comparable to that of compound II.

Design, synthesis and evaluation of malonic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. Phosphotyrosine (pTyr) is the substrate for PTP1B dephosphorylation. Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr, and novel malonic acid derivatives 1-7 were designed, synthesized and evaluated as PTP1B inhibitors. Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 micromol x L(-1), respectively.

Design, synthesis and evaluation of novel 2H-1, 4-benzodiazepine-2-ones as inhibitors of HIV-1 transcription / 药学学报

HIV-1 trans-activator of transcription (Tat) plays a critical role in HIV-1 transcription. Based on the beta-turn motif present in HIV-1 Tat, a series of novel benzodiazepine analogs were designed as beta-turn mimetics and prepared from p-chloro-nitrobenzene/2-phenylacetonitrile, p-toluidine/benzoyl chloride, or (Z)-7-nitro-5-phenyl-1H-benzo[e][1, 4]diazepin-2(3H)-one (nitrazepam) through different synthetic routes. Preliminary biological evaluation indicated that compound 30 exhibited inhibitory activity on HIV-1 tat-mediated LTR transcription with EC50 of 25.0 micromol x L(-1) and showed no obvious cytotoxic effects on TZM-BI cells under the concentration of 100 micromol x L(-1).

Advances in novel anti-HIV-1 drugs and drug candidates: 2005-2008 / 药学学报

HIV and AIDS remain as the crucial global health concern, therefore, research and development of novel anti-HIV-1 chemical therapeutics is still of paramount significance, which may be illuminated by cases of successful marketed drugs. Herein, we document the discovery and biological profile of new anti-HIV-1 drugs approved by FDA between 2005 and 2008 and some drug candidates are also discussed.