A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3 T lymphocytes re-distribution by inducing lymphocytes' homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment.

Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates

FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (-) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized a convergent route using the key and optically pure building block , which was first synthesized asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound showed higher phosphorylation rates in both rats and humans than the parent compound, whereas compound showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds and both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.

Comparison of conservative treatment and full thread hollow screw for treatment of Ekrol 2 fracture of the fifth metatarsal bone / 中华骨科杂志

Objective To compare the curative effect of conservative treatment and full thread hollow screw in the treatment of Ekrol 2 fracture of the fifth metatarsal bone.Methods From April 2013 to May 2015,42 patients with avulsion fractures of the fifth metatarsal basement of type 2 fractures in Ekrol division were treated in our hospital.23 patients underwent full thread hollow screw surgery (surgical treatment group),and there were 12 males and 11 females,with an average age of 43.4±9.2 years,and the fracture displacement length was 2.3±0.2 mm.19 patients treated with plaster fixation (conservative group),including 10 males and 9 females,with an average age of 45.7±8.9 years and fracture displacement length was 2.1±0.2 mm.During follow-up,X -ray examination was performed to evaluate the time of fracture healing and forefoot score of American Orthopaedic Foot and Ankle Society (AOFAS),visual analogue score (VAS) and quality of life questionnaire (SF-36) were compared between the two groups.Results All 42 patients were followed up for 12 to 24 months with an average of 18 months.At the latest follow-up,the fracture healing time of the surgical group was 9.3±2.0 weeks,with AOFAS score of 84.1±3.9,VAS score of 0.1±0.2,and the SF-36 score of 95.1±2.9 points,and the shortening of length after treatment was 2.1±2.5 mm;the average healing time of the conservative treatment group was 12.2±2.1 weeks,with the average AOFAS score of 84.2±4.2 points,and the average VAS score of 0.2±0.2 points,the average SF-36 score of 94.1 ±5.2 points,and the shortening of length after treatment was 0.4±2.5 mm.The results of each short-term score and the shortening of the length of the fracture after treatment was statistically significant.The results of the mid-and long-term scores showed no significant difference between the two groups;the fractures of both groups reached bone healing.3 cases of sural nerve stimulation occurred in the operation group,while 1 case occurred in the conservative group.Abnormal healing occurred in 2 cases of conservative treatment,and the fractures of the surgical treatment group were anatomic reduced.Conclusion Usingfull thread hollow screwfor the treatment of Ekrol 2 fracture of the fifth metatarsal bone is better than the conservative treatment in the short term,but there is no significant difference in the long-term effect.

Synthesis of a new metabolite of buagarofuran(AF-5) / 中国药科大学学报

@#It has been reported that buagarofuran(AF-5)as an anxiolytic drug. It possesses a structural feature including α-agarofuran and the n-butyl side chain. Recently, there is a new metabolite found in clinical study, which is hypothesized that the n-butyl side chain has been oxidized to carboxylic acid. In order to confirm its structure, the target compound was prepared from(4aR, 7R, 8aR)-8a-hydroxy-7-(2-hydroxypropan-2-yl)-4a-methyloctahydronaphthalen-2(1H)-one in a six-step reaction with an overall yield of 16. 7%. The structure is confirmed by NMR and MS.

Anti-rejection study in mice skin transplantation of a novel immunosuppressant SYL934 / 中国药理学通报

Aim To determine the effect of SYL934 , a novel immunosuppressant, on skin allograft rejec-tion. Methods HTRF-IP1 assay was used to evaluate the agonistic activity of SYL934-P, the active form of SYL934 in vivo, on S1P1 and S1P3 in vitro. SD rat peripheral blood lymphocytes ( PBL ) test and heart rate test was used to assess the in vivo immunosuppres-sive effect and heart rate effect of SYL934 . Mice skin graft transplantation experiment was used to observe the effect of SYL934 on skin allograft refection. ResultsSYL934-P selectively activated S1 P1 but not S1 P3 in vitro. Single orally administration of SD rats with SYL934 decreased the PBL significantly and played an obviously immunosuppressant role, but did not affect the heart rate. Daily orally administration of mice with SYL934 significantly increased the survival rate of al-lografts of skin slice in mice. Conclusion SYL934 has great selectivity in vitro and good activity in vivo, which indicated it potential use as an anti-rejection drug in skin transplantation.

Design, synthesis and biological evaluation of fingolimod analogues containing diphenyl ether moiety / 药学学报

A novel series of fingolimod analogues containing diphenyl ether moiety were designed and synthesized based on the modification of immunosuppressive agent fingolimod used in the treatment of multiple sclerosis. Compounds were evaluated in vivo for lymphopenic activity and heart rate affection. Most compounds showed moderate lymphopenic activity. It is worth noting that compounds 6c, 6d and 14c-14e showed considerable immunosuppressive activities comparable to fingolimod. And compound 14e had no effect on heart rate.

Effect of a novel selective S1P1 agonist, Syl948, on mouse skin transplantation / 药学学报

Syl948 is a synthesized selective S1P1 agonist with novel structure. HTRF-IP1 test indicated that Syl948-P, the active form of Syl948 in vitro, has strong activity against S1P1 (EC50: 83 +/- 16 nmol x L(-1)), but its effect on S1P3 was very weak (EC50: 1 026 +/- 90 nmol x L(-1)). In SD rats, oral administration of Syl948 10 mg x kg(-1) significantly decreased the peripheral blood lymphocytes (PBL), with the maximal PBL inhibition rate of 63%, which was as similar as equal dose of fingolimod (FTY720). Oral administration of Syl948 10 mg x kg(-1) had no effect on heart rate of SD rats, which was better than FTY720. Daily oral administration with Syl948 (2 or 4 mg x kg(-1)) significantly prolonged the survival time of the allografts of skin slice on mice. In summary, the above results demonstrated that Syl948 has great selectivity in vitro and good activity in vivo, which indicated its potential use as an anti-rejection drug in skin transplantation.

Synthesis and in vitro antitumor activities of novel benzyl urea analogues of sorafenib / 药学学报

A novel series of benzyl urea analogues based on the structural modification of sorafenib were synthesized. Their in vitro antitumor activities against MX-1, HepG2, Ketr3 and HT-29 were evaluated using the standard MTT assay. While several target compounds showed inhibitory activity against multiple cancer cell lines, compound 9 was of particular interest, demonstrating IC50 values (5.69-13.6 micromol x L(-1)) comparable to those of sorafenib. Furthermore, compounds 20 and 23 showed more potent inhibitory activity against HT-29 and MX-1 when compared to sorafenib. In particular, compound 20 bearing the N-3-pyridyl moiety not only exhibited greater inhibitory activity against HT-29 cell line (IC50 3.82 micromol x L(-1)), but also had improved solubility at pH 7.2, is worthy of further investigation as a lead to identify novel antitumor agents.

Synthesis and anti-tubercular activity of novel alkyl substituted riminophenazine derivatives / 药学学报

A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5-dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization.

Design, synthesis and in vitro activity of glycinamide-bearing compounds as DPP-IV inhibitors / 药学学报

To research the structure-activity relationship (SAR) of glycinamide-bearing compounds that used as inhibitors of dipeptidyl peptidase IV (DPP-IV), P32/98 and compound A were chosen as the leading compounds, heterocycles containing nitrogen atom were introduced to form amide, and different residues on a-position of carbonyl were designed. The nineteen designed compounds were synthesized by a simple route and were evaluated as inhibitors of DPP-IV. All of the structures were characterized by 1H NMR and HRMS. The preliminary SAR result was obtained.

DIAGNOSIS AND TREATMENT OF CYSTICERCOSIS OF CEREBRAL VENTRICLES / 中国寄生虫学与寄生虫病杂志

31 patients with cysticercosis of cerebral ventricles verified by operation or pathological investigation were reported. All patients were between 7 and 64 years of age and 14 were females. All had a single cyst. Since 29 patients (94%) were without a history of intestinal taeniasis, it was proposed that most patients of cysticercosis of cerebral ventricles were caused by hetero-infection and the entrance of Cysticercus into brain ventricle was through choroid plexus along the cerebro-spinal fluid. This is probably the reason why it occurs mostly in the 4th ventricle. The clinical manifestation of cysticercosis of cerebral ventricles were paroxysmal headache and vomiting caused by increased intracranial pressure. Ventricu-lography and CT scanning have considerable diagnostic value. Removal of Cysticercus by surgical operation is successful (Figs. 1 - 8).