Hypha Discovery Ltd

Our latest blog post explores the metabolism of muvadenant, inspired by a recent paper from Jonny Nachtigall and colleagues. Check out "When spirocycles become metabolic soft spots" at https://lnkd.in/e-yQuUMU! Spirocycles can bring valuable three-dimensionality, tune physicochemical properties and even improve metabolic stability. But what happens when the spirocycle itself becomes a weak point? Muvadenant offers an interesting case study, with metabolism studies revealing oxidative ring opening across two different ring systems. In this article, we explore how spirocycles might be metabolised and ask what this means for medicinal chemists designing metabolically robust drug candidates using these moieties. Source paper: Nachtigall et al. Preclinical pharmacokinetics and biodistribution of the dual adenosine A2A/A2B inhibitor muvadenant (M1069) in rats. Xenobiotica. 2026:1–10. doi: 10.1080/00498254.2026.2720770 #drugmetabolism #drugdesign #medicinalchemistry

Biocatalysis is a game-changer for accessing metabolites of more complex small molecules. In our last newsletter at https://lnkd.in/eTK_99fy we looked at MetID of the PROTAC tool compound MZ1 which is subject to oxidative metabolism across the three structural regions. Focussing in on metabolism in the JQ1 warhead, CYP2C8 and PolyCYP196 best produced the main oxidised metabolite M14. We now have an update! Scale-up of the PolyCYP196 reaction provided 2.6mg of pure M14 for structure elucidation by NMR spectroscopy to reveal selective hydroxylation in the thienotriazolelodiazepine core of the JQ1 warhead.

Is your drug metabolised by gut bacteria? We've completed a number of studies for clients who needed to identify major gut metabolites, and the stability of parent / metabolites in a faecal matrix. Read more at https://lnkd.in/enQX8_rq

Glucuronides have long been considered “innocuous” in nature. However, there is growing interest in glucuronides as mediators of DDIs. In our Paper Pick this month, we feature an industry perspective on in vitro studies recommended for investigating UGT mediated DDIs, written by David Stresser and Michael Zientek. Read more at https://lnkd.in/e43GWA3F #drugdiscovery #drugmetabolism #ddis #ugts #glucuronides

Here we highlight a major metabolite with a prolonged plasma half-life first detected in the human mass balance study. This open access paper by scientists at Merck KGaA describes generation, identification and evaluation of a major hydroxylated metabolite (M493) of xevinapant in which Hypha Discovery later generated the reference standard by microbial biotransformation. Although M493 was just under the 10% cut off in the human mass balance study, its longer half life in plasma warranted closer scrutiny of the metabolite. Interestingly the metabolite was not detected during in vitro profiling before the human mass balance study, likely due to its MS behaviour and in source water loss. Switching polarity was key to detection of the intact molecule. However fragment ions were not diagnostic and NMR was needed for full structural assignment. Read more at https://lnkd.in/evpys64U

New webinar alert! Join us for a 30-minute live webinar on Thursday 19th March to discover how Hypha uniquely integrates LC-MS/MS-based MetID with scalable metabolite synthesis and definitive structure confirmation by NMR spectroscopy. This enables metabolites to be made, identified and tested early on. Register for one of 2 time options at https://lnkd.in/eyPdxi-k