Renzulli Cecilia, Nash Mike, Wright Mark, Thomas Steven, Zamuner Stefano, Pellegatti Mario, Bettica Paolo, Boyle Gary
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Research and Development, Verona, Italy.
Drug Metab Dispos. 2011 Feb;39(2):215-27. doi: 10.1124/dmd.110.035386. Epub 2010 Nov 2.
N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [(14)C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization. NMR spectroscopy was also used to further characterize certain metabolites. Elimination of drug-related material was almost complete over a 9-day period, occurring principally via the feces (79%), whereas urinary excretion accounted only for 12% of total radioactivity. Mean apparent half-life (t(1/2)) of plasma radioactivity was notably longer (39.3 h), with respect to that of unchanged SB-649868 (4.8 h), suggesting the presence of more slowly cleared metabolites. SB-649868 and an unusual hemiaminal metabolite, M98 (2-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-3,5-dihydroxy-3,4-dihydro-1(2H)-isoquinolinone; GSK2329163), resulting from oxidation of the benzofuran ring and subsequent rearrangement, were the principal circulating components in plasma extracts. Two additional minor metabolites were also observed: a benzofuran ring-opened carboxylic acid M25 ([2-({[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]amino}carbonyl)-6-hydroxyphenyl]acetic acid; GSK2329158) and an amine metabolite (M8). SB-649868 was extensively metabolized, and only negligible amounts were excreted unchanged. The principal route of metabolism was via oxidation of the benzofuran ring with the resultant M25 being the principal metabolite in excreta, representing at least 12% of the administered dose across urine and feces.
N-[[(2S)-1-[[5-(4-氟苯基)-2-甲基-4-噻唑基]羰基]-2-哌啶基]甲基]-4-苯并呋喃甲酰胺（SB-649868）是一种正在研发用于治疗失眠的新型食欲素1和2受体拮抗剂。在8名健康男性受试者中采用开放标签研究设计，单次口服30mg后测定[(14)C]SB-649868的处置情况。给药后频繁采集血液、尿液和粪便样本，通过高效液相色谱-质谱联用离线放射性检测对样本进行分析，以进行代谢物谱分析和表征。核磁共振光谱也用于进一步表征某些代谢物。药物相关物质在9天内几乎完全消除，主要通过粪便排出（79%），而尿液排泄仅占总放射性的12%。血浆放射性的平均表观半衰期（t(1/2)）明显更长（39.3小时），相对于未变化的SB-649868（4.8小时）而言，这表明存在清除更慢的代谢物。SB-649868和一种不寻常的半缩醛胺代谢物M98（2-[((2S)-1-{[5-(4-氟苯基)-2-甲基-1,3-噻唑-4-基]羰基}-2-哌啶基)甲基]-3,5-二羟基-3,4-二氢-1(2H)-异喹啉酮；GSK2329163），由苯并呋喃环氧化并随后重排产生，是血浆提取物中的主要循环成分。还观察到另外两种次要代谢物：一种苯并呋喃环开环的羧酸M25（[2-({[((2S)-1-{[5-(4-氟苯基)-2-甲基-1,3-噻唑-4-基]羰基}-2-哌啶基)甲基]氨基}羰基)-6-羟基苯基]乙酸；GSK2329158）和一种胺类代谢物（M8）。SB-649868被广泛代谢，仅极少量以原形排泄。主要代谢途径是通过苯并呋喃环的氧化，产生的M25是排泄物中的主要代谢物，在尿液和粪便中占给药剂量的至少12%。
