Poster presented by Julia Shanu-Wilson on “Oxidized Metabolites and Unusual Conjugates of AZD9496 formed by microbial biotransformation” at the ISSX/MDO 2022 meeting in Seattle, September 2022.
Poster presented by Sam Coe on “PolyCYPs: Biocatalytic Tools for the Optimisation of Drug Leads” at the RSC Chemistry Meets Biology Meeting in London, September 2022.
Poster presented by Liam Evans at Drug Discovery Chemistry 2022 on “Routes for Synthesis of Metabolites of Ruxolitinib and Epacadostat”, April 2022.
Often several strategies are needed to access all key metabolites observed during drug development programs. Hypha has developed a “one-stop metabolite shop” scheme, which utilizes a combination of biological and chemical techniques in order to fulfil requirements to access any type of metabolites. The one-stop metabolite concept offers a parallel or sequential screening step to identify the most productive and cost-effective method to produce target metabolites. Depending on the type and quantity of metabolite required, a combination of chemical synthesis, mammalian S9, microbial biotransformation and recombinant phase I enzymes can be employed. Once the optimal production system is identified, the method can be scaled up to provide up to tens of grams of purified metabolites.
Introducing oxygen into a drug candidate late in the optimisation process has several applications including exploration of SAR (structure-activity relationships) and the ability to access derivatives that may possess superior properties such as improved metabolic stability and LLE (ligand-lipophilicity efficiency). Biocatalysis can provide access to chemical space in a complementary manner to chemical synthesis and provide a “one-experiment” solution to accessing multiple derivatives in parallel. This poster illustrates the application of a new biocatalysis kit, PolyCYPs®, to enable parallel synthesis of hydroxylated derivatives of drugs.
In recent years, FDA guidance has advised initiating human metabolite profiling earlier in drug development, emphasizing the importance of metabolite identification and quantification to evaluate a drug metabolite’s safety and pharmacological activity. Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator in Phase 2 clinical trials for diabetic nephropathy and heart failure with preserved ejection fraction (HFpEF). During studies on metabolism of praliciguat in preclinical species and in human hepatocytes, a prominent direct O-glucuronide metabolite was detected.
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Hypha Discovery is a UK-based CRO supporting pharmaceutical and agrochemical companies worldwide through the production of metabolites and new derivatives of drugs and agrochemicals in discovery and development.