Pharmacokinetics and tissue distribution of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; a novel ALK5 inhibitor and a potential anti-fibrosis drug.

Abstract

The authors investigated the pharmacokinetics and metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1130), a novel ALK5 inhibitor, which suppresses renal and hepatic fibrosis, and also exerts anti-metastatic effects on breast cancer-bearing MMTV-cNeu mice model. Plasma half-lives of orally administered IN-1130 were 62.6 min in mice, 76.6 +/- 10.6 min in dogs, 156.1 +/- 19.3 min in rats, and 159.9 +/- 59.9 min in monkeys. IN-1130 showed a high apparent permeability coefficient (P(app)) of (45.0 +/- 2.3) x 10(-6) cm s(-1) in in vitro permeability tests in a Caco-2 cell monolayer model. The bioavailability of orally administered IN-1130 was 84.9% in dogs and 34.4% in monkeys (oral dose, 5.5 mg kg(-1)), 11.4% in rats and 8.95% in mice (oral dose, 50.3 mg kg(-1)), respectively. Orally given IN-1130 was readily distributed into liver, kidneys and lungs. The major metabolite of IN-1130 (M1) was detected in the systemic circulation of rat and mouse and was purified and tentatively identified as 3-((4-(3-hydroxyquinoxaline-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide or 3-((4-(2-hydroxyquinoxalin-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide. The highest levels of M1 were found in liver. The results of this study suggest that IN-1130 has the potential to serve as an effective oral anti-fibrotic drug.

• Authors: Y W Kim, Y K Kim, J Y Lee, K T Chang, H J Lee, D-K Kim, Y Y Sheen
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 38 Issue 3 Pg. 325-39 (Mar 2008) ISSN: 0049-8254 [Print] England
• PMID: 18274960 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide
• Benzamides
• Enzyme Inhibitors
• Imidazoles
• Quinoxalines
• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, mouse
• Tgfbr1 protein, rat

Topics

• Administration, Oral
• Animals
• Benzamides (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Biological Transport (drug effects)
• Caco-2 Cells
• Chromatography, Liquid
• Dogs
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Half-Life
• Haplorhini
• Humans
• Imidazoles (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Injections, Intravenous
• Magnetic Resonance Spectroscopy
• Male
• Mass Spectrometry
• Mice
• Models, Biological
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Quinoxalines (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Tissue Distribution (drug effects)