Metabolism, pharmacokinetics and excretion of the GABA_Areceptor partial agonist [¹⁴C]CP-409,092 in rats

Abstract

The metabolism and excretion of a GABA(A) partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [(14)C]CP-409,092. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15 mg kg(-1), respectively, were characterized by high clearance of 169 + or - 18 ml min(-1) kg(-1), a volume of distribution of 8.99 + or - 1.46 l kg(-1), and an oral bioavailability of 2.9% + or - 3%. Following oral administration of 100 mg kg(-1) [(14)C]CP-409,092, the total recovery was 89.1% + or - 3.2% for male rats and 89.3% + or - 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48 h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.

Understanding the clinical pharmacokinetics of a GABAApartial agonist by application ofin vitrotools

“…These results provided strong evidence that the metabolism of (1) was mediated by MAO-A, not CYP450 or MAO-B. The formation of M6 in vitro is consistent with its formation in rats dosed 100 mg/kg of 14 C(1) (Kamel et al, 2010). MAO enzymes are present not only in liver but in several extra-hepatic tissues (Kalgutkar et al, 2001), thus the observation of MAO-A mediated metabolism of (1) in human hepatocytes and HLM likely represents only a small capacity of the total contribution of this enzyme to clearance of (1) in vivo and also likely contributes to the unanticipated low exposure.…”

“…rat (Kamel et al, 2010) suggested multiple possible clearance mechanisms of (1) including both oxidative metabolism as well as a major elimination pathway via the fecal route as unchanged 14 C(1). The pharmacokinetic profile of (1) in humans was unexpected since studies done to characterize the metabolism and disposition in animals did not offer any indication that (1) would show low oral exposure.…”

Functionalization of tetrahydroindol-4-one derivatives

“…Ці сполуки приваблють спеціалістів в галузі медичної хімії як міметики індолу з великою долею sp 3 -гібридизованих атомів, адже заміна плоского каркасу ациклічними фрагментами є загальною стратегією, яка сприяє оптимальному зв'язуванню з активними центрами ферментів та забезпечує кращу розчинність субстанцій [5]. Серед похідних піролоциклогексанонів відомий антипсихотичний препарат моліндон [6], агоніст ГАМК рецепторів для лікування тривожних станів [7] та потужний інгібітор теплового шоку специфічного білка при лікуванні раку [8]. Саме реакційна здатність пірольного циклу та карбонільної групи циклогексенового фрагмента зумовлюють цінність 4,5,6,7тетрагідроіндол-4-онів як потенційних будівельних блоків для синтезу важливих структур для потреб медичної хімії та спектроскопічних досліджень.…”

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

“…In the process, the amine is converted to an unstable imine intermediate, which is hydrolyzed non-enzymatically to aldehyde or ketone. Despite the commonalities, these enzymes are biochemically differentiated by their substrate and inhibitor specificities (Johnston, 1968;Murphy, 1978;Cawthon and Breakefield, 1979;Trevor et al, 1987;Waldmeier, 1987;Janssens de Varebeke et al, 1990;Nair et al, 1993;Dixon et al, 1994;Kopin, 1994;Tipton, 1994;Hauptmann et al, 1996;Youdim et al, 2001;Caccia et al, 2006;Kamel et al, 2010;Finberg and Rabey, 2016). Representative substrates and inhibitors of MAO A and B are shown in Supplementary Figure S2.…”