P10 - Use of Microbial Biotransformation to Produce Scalable Quantities of a Glucuronidated Metabolite of the Clinical Stage Soluble Guanylate Cyclase Stimulator Praliciguat
Presented at: ISSX meeting, Portland 2019
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.
Initial attempts by Cyclerion to isolate the metabolite in rat bile, via administration of praliciguat to bile duct-cannulated rats, lacked scalability and resulted in low yields. Access to larger quantities of this glucuronide metabolite for structure elucidation and pharmacological activity was achieved through microbial biotransformation of the parent compound. The purified glucuronide metabolite produced by the actinomycete strain was used as a quantitative analytical standard for clinical sample analysis and for other pharmacological and DMPK studies.