A double-blind, placebo-controlled, randomized multiple dose phase 1b trial of a CDK4/6 inhibitor, TCK-276, in patients with active rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and efficacy (as an exploratory endpoint) of TCK-276, a novel CDK4/6 inhibitor, after multiple oral doses for 7 days in patients with active RA. METHODS: This multicentre, randomized, placebo-controlled, dose-ascending, double-blind, phase 1b, multiple-dose study included 32 patients with active RA in 4 cohorts of 8 patients (6 active and 2 matching placebo), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily). The doses of TCK-276 were 10, 25, 75, and 175 mg/day. Safety and pharmacokinetic endpoints, and exploratory disease activity parameters for RA were assessed. RESULTS: There were no deaths, serious adverse events, notable clinically meaningful laboratory findings (including hematological changes), clinically meaningful vital sign changes, or clinically meaningful electrocardiogram or cardiac telemetry changes. TCK-276 was rapidly absorbed and the half-life time ranged approximately from 6 to 12 hours. No obvious accumulation was observed, and the increase in TCK-276 exposure was dose proportional. At day 7, DAS28-CRP responses (EULAR good or moderate responses) were observed in 40%, 80%, and 66.7% at 25, 75, and 175 mg/day TCK-276, respectively, versus 12.5% in placebo; ACR20 responses were 33.3%, 60%, and 50% respectively, versus none in placebo. CONCLUSION: TCK-276 (≤175 mg) was well tolerated with no clinically meaningful safety signals in patients with active RA. Together with the preliminary efficacy (≥25 mg/day), these data warrant further study of TCK-276 for the treatment of active RA. TRIAL REGISTRATION: ClinicalTrails.gov, NCT05437419.

Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator.

Glucokinase activators are regarded as potent candidates for diabetes treatment, however, in clinical studies on patients with type 2 diabetes, a diminishing efficacy was observed after chronic treatment with them. The mechanism of this reduction has not been elucidated, and whether it is a class effect of glucokinase activators remains inconclusive. Here, we firstly identified a diabetic animal model that shows the diminished efficacy after long-term treatment with MK-0941, a glucokinase activator that exhibited diminished efficacy in a clinical study, and we analyzed the mechanism underlying its diminished efficacy. In addition, we evaluated the long-term efficacy of another glucokinase activator, TMG-123. Goto-Kakizaki rats were treated with MK-0941 and TMG-123 for 24 weeks. The results showed that glycated hemoglobin A1C levels and plasma glucose levels decreased transiently but increased over time with the continuation of treatment in the MK-0941-treated group, while decreased continuously in the TMG-123-treated group. Only in the TMG-123-treated group, higher plasma insulin levels were shown at the later stage of the treatment period. For the mechanism analysis, we conducted a hepatic enzyme assay and liver perfusion study in Goto-Kakizaki rats after chronic treatment with MK-0941 and TMG-123, and revealed that, only in the MK-0941-treated group, the activity of glucose-6-phosphatase was increased, and hepatic glucose utilization was decreased compared to the non-treated group. These data indicate that disruptions in hepatic glucose metabolism are involved in the diminished efficacy of glucokinase activators.

Ex Vivo Method to Simultaneously Evaluate Glucose Utilization, Uptake, and Production in Rat Liver.

A novel ex vivo method to simultaneously evaluate hepatic glucose utilization, uptake, and production was developed in rats. The right lateral lobe of the liver was perfused with Krebs-Henseleit bicarbonate buffer containing 5 mmol/L uniformly labeled 13C-glucose ([U-13C]-glucose). The whole glucose concentration in the perfusate was measured by colorimetric assay, and the concentrations of [U-12C]-glucose (natural isotope) or [U-13C]-glucose were estimated on the basis of the abundance ratio of [U-12C]-glucose or [U-13C]-glucose, which were measured by GC-MS. The difference in whole glucose and [U-13C]-glucose concentrations between the baseline and effluent perfusate represents hepatic glucose utilization and glucose uptake, respectively. The [U-12C]-glucose concentration in the effluent perfusate corresponds to hepatic glucose production. With this method, we clarified the precise mechanism that underlies the hepatic impairment of diabetic animals and pharmacological effects of anti-diabetic agents. Thus, this method is useful for the pathophysiological and pharmacological research of type 2 diabetes.

TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models.

Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues. TMG-123 selectively activated GK enzyme activity without increasing Vmax. TMG-123 improved glucose tolerance without increasing plasma insulin levels in both insulin-deficient (Goto-Kakizaki rats) and insulin-resistant (db/db mice) models. The beneficial effect on glucose tolerance was greater than results observed with clinically available antidiabetic drugs such as metformin and glibenclamide in Zucker Diabetic Fatty rats. TMG-123 also improved glucose tolerance in combination with metformin. After 4 weeks of administration, TMG-123 reduced the Hemoglobin A1c levels without affecting liver and plasma triglyceride levels in Goto-Kakizaki rats and Diet-Induced Obesity mice. Moreover, TMG-123 sustained its effect on Hemoglobin A1c levels even after 24 weeks of administration without affecting triglycerides. Taken together, these data indicate that TMG-123 exerts glucose-lowering effects in both insulin-deficient and -resistant diabetes, and sustains reduced Hemoglobin A1c levels without affecting hepatic and plasma triglycerides even after chronic treatment. Therefore, TMG-123 is expected to be an antidiabetic drug that overcomes the concerns previously reported with other GK activators.

Design, synthesis, evaluation and QSAR analysis of N(1)-substituted norcymserine derivatives as selective butyrylcholinesterase inhibitors.

We synthesized a series of N(1)-substituted norcymserine derivatives 7a-p and evaluated their anti-cholinesterase activities. In vitro evaluation showed that the pyridinylethyl derivatives 7m-o and the piperidinylethyl derivative 7p improved the anti-butyrylcholinesterase activity by approximately threefold compared to N(1)-phenethylnorcymserine (PEC, 2). A quantitative structure-activity relationship (QSAR) study indicated that logS might be a key feature of the improved compounds.

Design, synthesis and evaluation of carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives as selective butyrylcholinesterase inhibitors.

We synthesized carbamate-modified (-)-N(1)-phenethylnorphysostigmine derivatives 3a-u and evaluated their anti-cholinesterase activities. In vitro evaluation showed that cyclohexylmethylcarbamate derivative 3u potently and selectively inhibits butyrylcholinesterase.