Safety, Tolerability, Pharmacokinetics, and Metabolism of Telacebec (Q203) for the Treatment of Tuberculosis: a Randomized, Placebo-Controlled, Multiple Ascending Dose Phase 1B Trial.

A phase 1b, randomized, placebo-controlled, double-blind, multiple ascending dose study (NCT02858973) was conducted to assess the safety, tolerability, and pharmacokinetics of the new antituberculosis agent telacebec (Q203). A total of 47 healthy adult subjects entered the study; 36 received telacebec, and 11 received placebo. Telacebec at doses of 20, 50, 100, 160, 250, and 320 mg was orally administered once daily with a standard meal for 14 days. Multiple oral doses of telacebec up to 320 mg daily for 14 days appeared to be safe and well tolerated by healthy adult subjects in this study. There were no deaths, serious adverse events, or subject discontinuations due to adverse events. Following oral doses of telacebec, the overall extent (AUCτ) and peak (Cmax) exposures of telacebec increased from 538.94 to 10,098.47 ng·h/mL and from 76.43 to 1502.33 ng/mL, respectively, with increasing telacebec doses from 20 mg to 320 mg. A steady state was achieved for plasma telacebec by day 12, and there was 1.9- to 3.1-fold accumulation in the extent of telacebec exposure after daily doses for 14 days. Analysis of plasma samples from the participants indicated that telacebec was the primary circulating entity with no significant metabolites. Three potential metabolites of telacebec have been identified, which may be relatively minimal compared to the parent drug. Consistent with findings from preclinical and previous single-dose clinical studies, these results also support the potential of telacebec for further development as a safe and effective agent for the treatment of tuberculosis.

Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects.

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 to 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 to 800 mg), telacebec plasma concentration reached the maximal plasma concentration (Cmax) in average 2.0 to 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration versus time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for Cmax. Moderate delay in Tmax (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support further investigation of telacebec for the treatment of tuberculosis.

The Assessment of Brain Volume Differences in Idiopathic Central Precocious Puberty Girls; Comparison of Age-Matched Girls and Normal Puberty Girls.

OBJECTIVE: Although there have been several studies on the neuroanatomical changes in idiopathic central precocious puberty (ICPP), the association between each brain region and ICPP has not yet been clearly elucidated. This study aimed to evaluate the difference in brain structure in ICPP compared with age-matched healthy controls and normal puberty controls, and additionally the correlation between brain volume difference and the luteinizing hormone (LH). MATERIALS AND METHODS: The study enrolled fifteen girls with ICPP, as well as 15 age-matched healthy girls and 15 normal puberty girls as controls. The subjects underwent a 1.5 Tesla Avanto MR Scanner. Anatomical T1-weighted images were acquired with a T1 spin-echo sequence. The volumes of total and regional brain were compared with each of the two control groups and analyzed through the paired T-test, and the brain region related to the peak LH level was also analyzed through a simple correlation test. RESULTS: The mean age of the ICPP group, age-matched group, and puberty group were 8.0 ± 0.9 years, 7.8 ± 0.9 years, and 11.9 ± 0.9 years, respectively. In our findings, the regional cerebral volumes in ICPP were different from age-matched controls. Compared with controls, ICPP showed a significant increase in gray matter (GM) volumes (the medial prefrontal cortex, superior parietal gyrus, supramarginal gyrus, angular gyrus, postcentral gyrus, superior occipital gyrus, cuneus, hippocampus, parahippocampal gyrus, posterior cingulate gyrus (PCgG), cerebellar cortex (Cb)) and in white matter (WM) volumes (the insular, caudate, splenium of corpus callosum (p < 0.001)). Especially, the GM volumes of the PCgG (r = 0.57, p = 0.03) and Cb (r = 0.53, p = 0.04) were correlated positively with LH concentrations stimulated by the gonadotropin-releasing hormone agonist. Compared to the normal puberty control, no significant difference in GM volume was found. CONCLUSIONS: This study showed the overall brain volumetric differences between ICPP girls and age-matched controls using voxel-based morphometric analysis, and further showed the correlation between brain volume and the sex hormone in ICPP. Through a comparison between the two groups, the cerebral development pattern of ICPP is similar to that of normal puberty, and these local differences in cerebral volume may affect social and congenital changes. These findings will be useful for understanding the neuroanatomical mechanisms on the specific morphological variations associated with ICPP.

GM-CSF and IL-4 produced by NKT cells inversely regulate IL-1ß production by macrophages.

Natural Killer T (NKT) cells are distinct T cell subset that link innate and adaptive immune responses. IL-1ß, produced by various immune cells, plays a key role in the regulation of innate immunity in vivo. However, it is unclear whether NKT cells regulate IL-1ß production by macrophages. To address this, we co-cultured NKT cells and peritoneal macrophages in the presence of TCR stimulation and inflammasome activators. Among cytokines secreted from NKT cells, GM-CSF enhanced IL-1ß production by macrophages via regulating LPS-mediated pro-IL-1ß expression and NLRP3-dependent inflammasome activation, whereas IL-4 enhanced M2-differentiation of macrophages and decreased IL-1ß production. Together, our findings suggest the NKT cells have double-sided effects on IL-1ß-mediated innate immune responses by producing IL-4 and GM-CSF. These findings may be helpful for a comprehensive understanding of NKT cell-mediated regulatory mechanisms of the pro-inflammatory effects of IL-1ß in inflammatory diseases in vivo.

Serendipitous discovery of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds.

Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of triazolothienopyrimidine (TTPM) compounds as potent HIV-1 replication inhibitors during a high-throughput screening campaign that evaluated more than 200,000 compounds using a cell-based full replication assay. Herein, we report the optimization of the antiviral activity in a cell-based assay system leading to the discovery of aryl-substituted TTPM derivatives (38, 44, and 45), which exhibited significant inhibition of HIV-1 replication with acceptable safety margins. These novel and potent TTPMs could serve as leads for further development.

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability.

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.