GRC 27864, novel, microsomal prostaglandin E synthase-1 enzyme inhibitor: phase 1 study to evaluate safety, PK and biomarkers in healthy, adult subjects

Abstract

and as Standardized Response Mean (SRM; mean score change divided by change standard deviation). Effect sizes were categorized as small 0.20e0.49, moderate 0.50e0.79 or large !0.8. Results: Complete longitudinal data for all three measures at all three time points were available for 2904 patients (75% women, mean age 64.2 years, mean BMI 27.8). The effect sizes for the physical component score of SF-12, the SF-6D and for the EQ-5D index at both 3 and 12 months were similar and around 0.4, Figure 1. The effect sizes for the mental component score of SF-12 and the EQ VAS were lower and around 0.1e0.2, Figure 1. The effect size for the pain VAS was higher at both time points and approaching 0.6. Mean values, ESs and SRMs for all three instruments are given in Table 1. Conclusions: In this head-to-head comparison, we found SF-12 PCS, SF-6D and EQ-5D to be similarly responsive at both 3 and 12 months. The physical component score of SF-12, SF-6D and the EQ-5D index were the more responsive measures, with effect sizes categorized as small. Both generic measures were sensitive to change over time, and hold the potential for evaluation of change in overall health status and for use in health economic evaluations following combined patient education and supervised exercise in patients with knee or hip OA.

Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition

“…mPGES-1 is highly upregulated in inflammation, making it a potential target for developing selective anti-inflammatory therapies that specifically inhibit PGE 2 production without affecting other prostaglandins, potentially reducing the risk of gastrointestinal and cardiovascular side effects accompanied by traditional COX inhibitors (Bergqvist et al, 2020). Efforts to progress selective mPGES-1 inhibitors have led to two candidates, LY3023703 (whose trials were halted due to hepatotoxicity) (Jin et al, 2018) and GRC27864 (currently in Phase 2 trials) (Sant et al, 2018).…”

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

“…Tus, selective inhibition of mPGES-1, which is the terminal enzyme responsible for the conversion of PGH 2 into PGE 2 , has been suggested as a safer therapeutic strategy without afecting the normal production of other prostaglandins related to the body's homeostasis [10,11]. Despite the high number of inhibitors identifed so far [12], however, only a few mPGES-1 inhibitors such as GRC-27864 (zaloglanstat) and GS-248 (vipoglanstat) have been tested in humans (Figure 1) [13,14].…”

Synthesis, in silico studies and cytotoxicity evaluation of novel 1,3,4-oxadiazole derivatives designed as potential mPGES-1 inhibitors

“…The compound LY3023703 has been reported as first one, entered the clinical trial [43]. Recently, Glenmark Pharmaceuticals developed dihydropyrido [4,3-d]pyrimidine a compound, which has entered phase I, clinical trial named GRC-27864 (Clinical Trials Identifier: NCT02179645) [44]. Compound 4b, a 5-arylmethylenebarbituric acid derivative was developed by Chang Guo Zhan's lab as an inhibitor of mPGES-1 enzyme [45].…”