No images? Click here Hypha DiscoveryWhat's New Q2 2024Focus Feature: N-glucuronides of pyrazoles N-glucuronides may emerge as disproportionate metabolites due to interspecies variability and higher rates of N-glucuronidation in humans. This is particularly relevant for some aromatic N-heterocycles metabolised by UGT1A4 and UGT2B10. Here we take a look at two major N-glucuronides formed by UGT1A4 that were needed for further studies. N-glucuronides by microbial biotransformation Camonsertib is metabolised by Phase I mechanisms and to a single glucuronide in human hepatocyte incubations. The point of attachment could not be pinpointed by LC-MS/MS or by prediction software. Whilst chemical synthesis resulted in two low yielding glucuronides, microbial biotransformation generated tens of mgs of the single specific N-glucuronide which matched to the human product, the structure of which was confirmed by NMR. Studies on the purified metabolite demonstrated stability under typical bioanalytical sample processing conditions. A paper describing this work was published earlier this year. N-glucuronides by late-stage chemical synthesis LEO compound 1 is also metabolised by both oxidation and conjugation with the pyrazole moiety glucuronidated to a major metabolite. Human liver S9 incubations provided a high conversion to the glucuronide and it was also possible to produce the metabolite by microbial biotransformation. However in order to make gram amounts of the metabolite, a late-stage chemical synthesis route was preferred. Deuterated metabolite was also synthesised using this method. Studies with the metabolite indicated excretion in the bile, hydrolysis and reabsorption of parent, but was thought not to lead to significant enterohepatic recirculation. Drug Discovery Today paper In this open access review paper out this month in Drug Discovery Today we delve into the critical role of metabolites in drug discovery and the impact of regulatory frameworks. We look into the reasons for metabolite synthesis, the timing, and the methods used for their identification. Case studies illustrate the importance of understanding metabolite profiles, and underscore the need for timely assessment of metabolites. Our latest blogsN-glucuronidation: The human element In this blog topic we look at why N-glucuronidation of small molecule drugs is important in human drug metabolism including the relevance of UGT1A4. We also comment on aspects related to the stability of N-glucuronides. Metabolism of FDA approved drugs Two blog articles cover interesting aspects around metabolism of small molecule drugs approved by the FDA in 2023. Part 1 looks at 9 drugs where there is mention of the involvement of active metabolites. Part 2 covers a subset of drugs metabolised by Phase II mechanisms. Paper picks this quarterBioisosteres for carboxylic acids Our highlighted paper for April 2024 discusses the reasons and strategies for replacing a carboxylic acid with a bioisostere. Of particular interest is the authors use of structural biology to explore neutral bioisosteres that rely on less commonly explored cation π-interactions. AO mediated toxicity Our highlighted paper for March 2024 looks at how chemists investigated and overcame anticoagulation mediated toxicity caused by a circulating aldehyde oxidase metabolite which was exacerbated by accumulation of the metabolite on repeat dosing. Metabolite Tales blogHave a look at our other blog articles we've published so far here. Stay tunedIf you're interested in keeping up with what's happening at Hypha Discovery, our blogs and paper picks, follow us on LinkedIn for regular updates. |