Efficacy and safety of Dimdazenil in the adult insomnia patients: a phase II randomized, multicenter, double-blind, placebo-controlled, and parallel-group study.

STUDY OBJECTIVES: To evaluate the efficacy and safety of Dimdazenil, a positive allosteric modulator with selectivity for α1, α5 subunit-containing GABAA receptors, on sleep variables in patients with insomnia disorder. METHODS: In this randomized, double-blind, placebo-controlled trial, adults (18-65 years) with insomnia disorder were randomized (1:1:1:1 to receive daily oral placebo, Dimdazenil (1.5, 2.5, or 5 mg) for 14 days. The primary efficacy outcome was the total sleep time (TST) on day 1/2 and day 13/14, measured by polysomnography. The secondary outcome measures included (1) latency to persistent sleep (LPS), sleep efficiency (SE), wake after sleep onset (WASO) and number of awakenings (NAW) on days 1/2 and day 13/14, and (2) the average subjective sleep latency (sSL), total sleep time (sTST), wake after sleep onset (sWASO) and number of awakenings (sNAW) recorded in sleep diary and sleep questionnaire, and the evaluation of insomnia severity index. Rebound insomnia, withdrawal, and treatment-emergent adverse events were also assessed. RESULTS: Of 569 patients screened, 288 (76.4% female) were randomized and received one dose. For the primary outcomes, TST was significantly improved in the Dimdazenil 1.5, 2.5, and 5 mg group compared with the placebo group at day 1/2, and significantly improved in the Dimdazenil 2.5 and 5 mg groups compared with the placebo group at day 13/14. The Least Squares Means (standard errors) and 95% Confidence Intervals for the three active doses compared to placebo are 25.5 (8.31), (9.16, 41.89) for the 1.5 mg dose; 17.4 (8.19), (1.29, 33.55) for the 2.5 mg dose; 22.8 (8.15), (6.72, 38.80) for the 5 mg dose on day 1/2. Corresponding data on day 13/14 are 7.6 (8.07), (-8.24, 23.53) and 19.3 (8.06), (3.43, 35.17) and 18.2 (7.95), (2.49, 33.80). LPS was significantly reduced in the Dimdazenil 5 mg group compared with the placebo group on day 1/2. SE was significantly improved in the Dimdazenil 1.5 and 5 mg group compared with the placebo group at day 1/2. In the subjective sleep parameters, sSL on average was significantly lower in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. sTST on average was significantly higher in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. The most common TEAEs were dizziness, vertigo, and weakness with no clinically relevant treatment-related serious adverse events. CONCLUSIONS: Dimdazenil of 1.5, 2.5, and 5 mg improved certain objective and subjective sleep outcomes in people with insomnia disorder, with a favorable safety profile. These findings suggested that Dimdazenil may represent a promising new treatment for insomnia disorder, a prevalent condition with limited effective and safe treatments available. CLINICAL TRIAL INFORMATION: A multicenter, randomized, double-blind, multidose, placebo parallel controlled phase II clinical study of EVT201 in the treatment of insomnia disorders (http://www.chinadrugtrials.org), with the number of CTR20150664.

Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach.

An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 µM), which exhibits much less toxicity toward normal cells (EC50 > 100 µM against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects.

A new strategy toward fused-pyridine heterocyclic scaffolds: Bischler-Napieralski-type cyclization, followed by sulfoxide extrusion reaction.

Method development was completed for a new strategy to obtain fused-pyridine heterocyclic scaffolds. The synthetic route entails a Bischler-Napieralski-type reaction as the key step, followed by a sulfoxide extrusion reaction. The reactions of 3-amino-2-arylthiopyridines or 3-amino-4-arylthiopyridines and carboxylic acids promoted by a Lewis acid such as SnCl4 yielded novel tricyclic pyridobenzothiazepines, which could be readily converted to their corresponding oxidized products via a sequence of sulfur oxidations and eventually to benzonaphthyridines via a sulfoxide extrusion. The synthetic strategy provides an efficient way to access libraries of novel structurally diversified heterocyclic compounds with potential pharmaceutical or biological activities.

Design and synthesis of a tetracyclic pyrimidine-fused benzodiazepine library.

Method development for a heterocyclic library which entails novel scaffolds of benzodiazepines fused with various heterocycles, such as pyrimidines, indolines, and tetrahydroquinolines, was accomplished. The new synthetic strategy is based on an electrophilic cyclization reaction involving an iminium intermediate formed by the corresponding aminopyrimidine with a carbonyl compound to give the desired heterocycles in high yields. Subsequent replacement of the chloro group in the resulted structures with a nucleophile, such as boronic acids, amines, alcohols and thiols, led to a library of privileged compounds with up to eight accessible diversity points.