Unexpected Major Metabolite of Iclepertin


Unexpected major human metabolite of iclepertin

There are several fascinating elements to the complex biotransformation of iclepertin, our paper pick for August 2023.

Iclepertin (BI 425809) is a small molecule inhibitor of the glycine reuptake transporter (GlyT1), under development by Boehringer Ingelheim for the treatment of cognitive impairment associated with schizophrenia. It has a US FDA Breakthrough Therapy Designation. Results so far have demonstrated iclepertin to be both safe and well tolerated in healthy individuals and in patients with schizophrenia.

There are two divergent pathways involved in the extensive metabolism of iclepertin, both of which each result in a major circulating metabolite, M232 and M530a. However, M232 only emerged as an unexpected major metabolite in plasma following extended multiple dose studies.

A transient carbinolamide is proposed as the source intermediate feeding both pathways. A “fast track” route involves opening of the carbinolamine to the aldehyde M528 followed by reduction to a primary alcohol M530a by carbonyl reductase CBR1. CYP3A can convert M530a back to M528, which then acts as a substrate for further biotransformations. Notably this includes oxidation by both aldehyde oxidase and CYP3A to M544, the most abundant metabolite in urine and proposed as a terminal circulating metabolite. Interestingly the most abundant metabolite in faeces is M546 which results from isoxazole ring opening of M544, potentially through the action of gut microbiota.

An alternative route from the carbinolamide intermediate involves a much slower oxidation by CYP3A to M526, proposed as a rate limiting step in the formation of the other major circulating metabolite, M232 from cleavage by plasma amidases. This dramatic difference in rate of metabolism meant that M232 was not observed during in vitro and single dose studies in humans. In addition, clearance of M232 is much slower than that of iclepertin resulting in accumulation of the metabolite.

The authors stress the importance of adequate sampling duration and rigorous metabolism studies to capture such slow-forming, long half-life metabolites.


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