CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4-Hydroxypiperidinol Metabolites.

The dual orexin receptor antagonist daridorexant was approved in 2022 in the USA and EU for the treatment of insomnia. The purpose of this study was the identification of its metabolic pathways and the human cytochrome P450 (P450) enzymes involved in its biotransformation. With human liver microsomes, daridorexant underwent hydroxylation at the methyl group of the benzimidazole moiety, oxidative O-demethylation of the anisole to the corresponding phenol, and hydroxylation to a 4-hydroxy piperidinol derivative. While the chemical structures of the benzylic alcohol and the phenol proved to be products of standard P450 reactions, 1D and 2D NMR data of the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring and suggested the disappearance of the pyrrolidine ring and formation of a new 6-membered ring. Its formation is best explained by initial hydroxylation of the pyrrolidine ring in 5-position to yield a cyclic hemiaminal. Hydrolytic ring opening then results in an aldehyde that subsequently cyclizes onto one of the benzimidazole nitrogen atoms to yield the final 4-hydroxy piperidinol. The proposed mechanism was substantiated using an N-methylated analogue, which might hydrolyze to the open-chain aldehyde but cannot undergo the final cyclization step. CYP3A4 was the major P450 enzyme responsible for daridorexant metabolism, accounting for 89 % of metabolic turnover.

Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/ Accelerator Mass Spectrometry.

BACKGROUND: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME). METHODS: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. RESULTS: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine. CONCLUSION: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.

Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines.

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.

Inhibitors of Plasmepsin II-potential antimalarial agents.

In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.