MIDD0301 is a high affinity positive allosteric modulator of GABAA receptors and has been shown to relax airway smooth muscle and reduce lung inflammation in several in vivo and ex vivo studies. It was found during metabolic investigations that MIDD0301 is stable towards phase I metabolism in the presence of mouse, rat, dog and human liver microsomes. However, MIDD0301 underwent three major Phase II conjugations, excreted in urine and feces in form of glucoside, glucuronide and taurine conjugates. In the presence of mouse liver and kidney S9, it was uncovered that MIDD0301 glucuronide was formed more rapidly than the corresponding glucoside. Glucuronidation was observed for liver S9, whereas glucosidation was observed only for kidney S9. Urine and feces samples collected with aid of a metabolic cage unveiled the excretion profile of MIDD0301 for IP, ORAL and IV administrations. For IV and IP administrations, more MIDD0301 glucoside than glucuronide was found, which were exclusively secreted in urine. For oral administration, the glucuronide was the major metabolite of MIDD0301. The MIDD0301 taurine conjugate was excreted exclusively in feces and observed predominantly for IP followed by IV and ORAL administrations. Based on the initial dose, up to 88.2 % was recovered as MIDD0301 and its metabolites, predominately during the first 24 hours. Furthermore, a 28 days repeated MIDD0301 dose study (200 mg/kg/day) showed no signs of accumulation of MIDD0301 or its metabolites in the mouse brain confirming the absence of CNS effects determined by rotarod during the course of the study.

Metabolic excretion profile of clinical asthma compound MIDD0301

ACS Spring Meeting 2021

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