Synthesis of N-glucuronides of pyrazole moieties in drugs. Poster presented at: 50th Open DMDG Meeting, York, UK and APA meeting Boston, USA.
Abstract
Glucuronidation is the most common phase II reaction observed in the metabolism of drugs in humans, involving conjugation of small molecules to glucuronic acid by UDP-glucuronosyltransferases (UGTs). N-glucuronides can be formed as a result of aliphatic and aromatic conjugations with pyrazole, pyridine, pyridazine, pyrrolidine, pyrimidine, imidazole, triazole, and tetrazole moieties all being susceptible ring structures.
Interspecies variability in N-glucuronidation is relatively high and is compounded by much higher rates of N-glucuronidation in humans. This is largely due to UGT1A4 and UGT2B10. This species difference can lead to the observation of disproportionate N-glucuronides during studies in humans.
This poster illustrates the use of late-stage chemical glucuronidation and microbial biotransformation to provide scalable quantities of UGT-1A4 mediated pyrazole-linked N-glucuronides of two clinical stage drugs for definitive structure elucidation by NMR and further testing of the metabolites.