Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine, a novel and selective p38α inhibitor: identification of an active metabolite in preclinical species and human liver microsomes

• Published in: Biopharmaceutics & drug disposition Vol. 27; no. 8; pp. 371 - 386
• Main Authors: Kalgutkar, Amit S., Hatch, Heather L., Kosea, Frederick, Nguyen, Hang T., Choo, Edna F., McClure, Kim F., Taylor, Timothy J., Henne, Kirk R., Kuperman, Alexander V., Dombroski, Mark A., Letavic, Michael A.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2006
• Subjects: inflammation; inhibitor; metabolite; p38; P450; pharmacokinetics; prediction
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.520

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 p38α, 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 (Vdss) ranging from 0.4–1.3 l/kg (2.4–26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague‐Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) 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 p38α in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu∼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 (IC50>50 µM). 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. Copyright © 2006 John Wiley & Sons, Ltd.