Structure-Activity Relationship (SAR): Effort Towards Blocking NGlucuronidation of Indazoles (PF-03376056) By Human UGT1A Enzymes

Kelly      Rose; Young-Sun      Yang; Richard      Sciotti; Hongliang      Cai

Abstract

GyrATPase is a cellular enzyme that has been used as an antibacterial target for treatment of nosocomial and community acquired bacterial infections. The leading chemical series targeted at inhibiting this enzyme, indazoles, were rapidly cleared in rats (CL > 70 mL/min/kg). The predominant metabolite identified in both urine and bile samples from a bile duct-cannulated study corresponded to direct glucuronidation of the parent compound and was excreted rapidly. Subsequently, a carefully designed analog was used to pinpoint the site of glucuronidation (N-glucuronidation) by incubation with rat hepatocytes and followed by mass spectrometry analysis. Reaction mapping with an array of recombinant UGT isozymes revealed that N-glucuronidation was predominantly catalyzed by the UGT1A family of enzymes. Based on the results, the following approaches were considered to reduce or eliminate glucuronidation: 1) adding sterically hindered substitutions on the phenyl ring of the indazole core; 2) changing the electron distribution by substituting with electrondonating or – withdrawing groups; 3) replacing the site of glucuronidation. The resulted compounds were evaluated in vitro in rat hepatocytes to assess their metabolic stabilities followed by in vivo efficacy studies in the murine peritonitis sepsis model (at 50 mg/kg) for selected compounds.

Keywords: N-glucuronidation, Indazoles, UGT1A

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