Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

Preclinical pharmacokinetics of a novel anti-c-Met antibody-drug conjugate, SHR-A1403, in rodents and non-human primates.

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody-drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys. 2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t1/2) of ADC ranged from 4.6 to 11.3 days in the three species. 3. Tissue distribution study in tumor-bearing mice showed high accumulation of 125I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug. 4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC. 5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR = 5 to 6 and DAR = 1, respectively, and therefore prompted selection of an appropriate DAR value (DAR = 2) for SHR-A1403 used in preclinical development and clinical trials. 6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.

[Experimental studies of therapeutic effect of Rheum officinale on acute pancreatitis].

OBJECTIVE: To investigate the therapeutic effect of Rheum officinale on acute pancreatitis. METHODS: Buffered sodium taurocholate (3% m/V) was injected into the pancreatico-biliary duct to induce acute pancreatitis. Death rate,coefficient of pancreas, serum amylyse (AMY), hemocuprein (SOD), TNF-alpha and IL-1beta level were examined at 6, 12 and 24 hours after operations. Pathology analysis were also obtained. RESULTS: Compared with corresponding pancreatitis groups,death rate, coefficient of pancreas, serum TNF-alpha and IL-1beta level of drug groups decreased remarkably (P < 0.05), while serum SOD level significantly increased (P < 0.01). Serum AMY level of drug groups increased at 6 h (P < 0.01), decreased at 12 h (P < 0.01) and had no statistics disparity at 24 h (P > 0.05) compared with respective pancreatitis group. Although score points of all drug groups were lower than corresponding pancreatitis groups, the growth tendency of both were similar. CONCLUSION: Rheum officinale Baill has the effect of prevention to pancreas pathological changes in the animal pattern, but not able to reverse the tendency.

Anti-diabetic effects of Panax notoginseng saponins and its major anti-hyperglycemic components.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases, such as hemostasis, edema and odynolysis. AIM OF STUDY: Our aim was to investigate the mechanisms of anti-hyperglycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects. MATERIALS AND METHODS: KK-Ay mice received daily intraperitoneal injections of PNS 200mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin, leptin levels, body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points. RESULTS: The PNS group had significantly lower FBGL, improved GT and smaller body weight incremental percentage after the 30-day treatment. Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment. CONCLUSIONS: PNS possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice.

[Effects of Panax notoginseng saponins on anti-hyperglycemic, anti-obese and prevention from kidney pathological changes in KK-Ay mice].

OBJECTIVE: To observe the effects of Panax notoginseng saponins (PNS) on anti-hyperglycemic, anti-obese and prevention from kidney pathological changes in a type 2 diabetic KK-Ay gene mice model. METHODS: All animals were divided into 4 groups: Normal control group (C57BL/6J mice) were treated by NS 10 mL/kg, KK-Ay mice were subdivided into 3 groups as DM administrated NS 10 mL/kg, PNS 50 mg/kg, PNS 200 mg/kg respectively. All the animals received daily intraperitoneal injections for 30 days consecutively. All of these following items were determined as the effect of PNS: fasting plasma glucose levels (FPG), intraperitoneal glucose tolerance, body weight, food intake, insulin resistance index (IRI), serum insulin, triglyceride (TG), cholesterol (CH) levels and contribution of glomerulus injury. RESULTS: On the 12th, 22nd and 30th day, PNS-treated group had significantly lower FPG and low body weight incremental percentage. After a 12-day treatment, glucose tolerance was significantly improved. On the 30th day the serum IRI and TG levels of PNS-treated group decreased significantly, and the development of the mice glomerular lesions was prevented significantly. All of these showed a dose-effect relationship. CONCLUSION: PNS has the effects of anti-diabetes, anti-obese and prevention from kidney pathological changes in type 2 diabetic KK-Ay mice.