(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding.

A group of α-anilinoketones, 2-aminoalcohols, α-anilinoesters and α-anilinoamides were successfully synthesized and characterized by NMR spectroscopy and mass spectrometry. The yields were, in general, moderate to good (up to 75.4%), except for the α-anilinoesters (16.9–35.6%). The α-halocarbonyl starting materials showed different chemical reactivities. α-Haloketones and α-chloroacetates afforded monoalkylation, while small α-chloroamides afforded dialkylation. Finally, NMR spectroscopy revealed interesting structural features about the 2-aminoalcohols and diphenylamides.

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GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.

Background Metabolic effects of integrase strand transfer inhibitors (INSTIs) have been reported. The FDA Adverse Event Reporting System (FAERS) is a publicly available database that captures spontaneously reported adverse events. The objective of this study was to evaluate the relationship between INSTIs and metabolic adverse events using the FAERS database. Methods FAERS data were queried from quarter 4 of 2007 through quarter 4 of 2019 and limited to adults. The Standardized MedDRA Query for ‘hyperglycaemia/new-onset diabetes mellitus’ (H/DM) was used to identify metabolic adverse events of interest. Weight gain was analysed as a separate event. Reporting odds ratios (RORs) and 95% CIs were calculated for the INSTI class and individual agents. Results Over 10.1 million FAERS reports were identified. Any INSTI was mentioned as a primary and/or secondary suspect agent in 18,400 (0.18%) reports (bictegravir: 1414 [0.01%]; dolutegravir: 7840 [0.08%]; elvitegravir: 4034 [0.04%]; raltegravir: 5551 [0.05%]). RORs (95% CI) for H/DM and weight gain for any INSTI were 1.20 (1.15–1.27) and 2.16 (1.96–2.38). For individual agents, RORs (95% CI) for H/DM and weight gain were as follows: bictegravir, 1.23 (1.10–1.37) and 6.82 (5.50–8.41); dolutegravir, 1.28 (1.19–1.39) and 1.86 (1.58–2.18); elvitegravir, 0.76 (0.56–1.02) and 1.63 (1.37–1.92); and raltegravir, 1.00 (0.90–1.11) and 3.29 (2.77–3.91). H/DM was noted in 159 bictegravir and 712 dolutegravir reports. Conclusion Overall, H/DM was associated with bictegravir and dolutegravir and weight gain with all INSTIs. Clinicians should know the potential relationship between INSTIs and metabolic effects and institute appropriate monitoring. This paper was previously presented META-INSTI: Metabolic Adverse Events Following Integrase Strand Transfer Inhibitor Administration in Spontaneous Adverse Event Reports. Platform Presentation. ID Week. Virtual 2020.