The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vd(ss)) ranging from 0.4-1.3 l/kg (2.4-26 l/m(2)) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m(2)) and Sprague-Dawley rats (7.65+/-1.08 ml/min/kg, 45.9+/-6.48 ml/min/m(2) in male rats and 3.15+/-0.27 ml/min/kg, 18.9+/-1.62 ml/min/m(2) in female rats) and moderate in beagle dogs (12.3+/-5.1 ml/min/kg, 246+/-102 ml/min/m(2)) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30-65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38alpha in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (f(u) approximately 0.1-0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC(50)>50 microM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent.

译文

6-(4-(2,5-二氟苯基) oxazol-5-yl)-3-异丙基-[1,2,4]-三唑并 [4,3-a] 吡啶 (1) 的处置,这是一种有效且选择性的丝裂原活化蛋白 (MAP) 激酶p38alpha抑制剂,在几种动物物种中被描述为支持其临床前安全性研究和潜在临床开发的选择。1在所有被检查的物种中表现出普遍有利的药代动力学特性。静脉注射 (静脉注射) 给药后,1在大鼠,狗和猴子中表现出0.4-1.3 l/kg (2.4-26 l/m(2)) 的稳态下低分布量 (Vd(ss))。食蟹猴的全身血浆清除率低 (6.00毫升/min/kg,72.0毫升/min/m(2)) 和Sprague-Dawley大鼠 (7.65 +/-1.08毫升/min/kg,45.9 +/-6.48毫升/min/m(2) 在雄性大鼠和3.15 +/-0.27毫升/min/kg,18.9 +/-1.62毫升/min/m (雌性大鼠2) 和比格犬中等 (12.3 +/-5.1毫升/min/kg,246 +/-102毫升/min/m(2)) 导致临床前物种的血浆半衰期为1至5 h。在大鼠 (30-65%) 中观察到中度至高生物利用度1,狗 (87%) 和猴子 (40%) 口服 (p.o.) 给药后与Caco-2通透性测定中1的体外吸收曲线一致。在大鼠中,口服药代动力学在研究的剂量范围内是剂量依赖性的 (5,50和100 mg/kg)。1在大鼠,狗,猴子和人类肝微粒体以及临床前物种的体内涉及细胞色素P450酶介导的氧化代谢。1在临床前物种和人类中的主要代谢命运涉及异丙基上的羟基化以产生三级醇代谢物2。在人类肝微粒体中,根据使用同工酶特异性抑制剂和重组CYP酶的反应表型分析判断,这种转化是由CYP3A4催化的。在各种体外测定中,代谢物2也显示出对p38alpha的抑制能力。1以及活性代谢物2与血浆蛋白中度至高度结合 (f(u) 大约0.1-0.33) 在大鼠中,小鼠,狗,猴子和人。1以及活性代谢物2没有表现出对五种主要细胞色素P450酶的竞争性抑制,即CYP1A2,2C9,2C19,2D6和3A4 (IC(50)>50微米)。总的来说,这些结果表明吸收,分布,1的代谢和排泄 (ADME) 概况在临床前物种中相对一致,并预测了人类潜在的有利药代动力学特性,支持其选择毒性/安全性评估研究以及在人类中作为抗炎剂的可能研究。

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