Preclinical pharmacokinetics, metabolism, and disposition of NXE0041178, a novel orally bioavailable agonist of the GPR52 receptor with potential for treatment of schizophrenia and related psychiatric disorders

The physico-chemical properties, protein binding, metabolism, permeability, transporter interactions, chemical toxicity, and drug-drug interaction potential of the novel GPR52 agonist NXE0041178 were characterised.NXE0041178 demonstrated high cellular permeability, little interaction with efflux transporters P-gp and BCRP, and extensive brain exposure in rodent, consistent with its intended use in CNS disorders.In vivo pharmacokinetic profiling in mouse, rat and monkey demonstrated that NXE0041178 was well-absorbed, with low clearance, a moderate volume-of-distribution and moderate terminal half-life. Oxidative metabolism was the major elimination pathway, with negligible renal or biliary excretion.NXE0041178 displayed good in vitro-to-in vivo correlation in metabolic clearance in preclinical species and low turnover in human in vitro metabolic systems, suggestive of a human pharmacokinetic profile commensurate with once-daily dosing.Early in vitro metabolite identification studies suggested similar metabolic pathways in human and preclinical species, but a distinct metabolic profile in dog.NXE0041178 caused weak heterotropic catalytic activation of CYP3A4, and weak transcriptional induction of CYP3A4 and CYP2B6. No reactive metabolites of NXE0041178 were detected, and no genotoxicity or clinically relevant inhibition of P450 Enzymes were observed.These findings extend our knowledge of the preclinical ADME profile of NXE0041178, supporting its continued development.

ADME; GPCR; GPR52; agonist; biotransformation; metabolism; pharmacokinetics; schizophrenia.