TY - JOUR T1 - Pharmacokinetic Optimization of 4-Substituted Methoxybenzoyl-Aryl-Thiazole (SMART) and 2-Aryl-4-Benzoyl-Imidazole (ABI) for Improving Oral Bioavailability JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.110.036616 SP - dmd.110.036616 AU - Chien-Ming Li AU - Jianjun Chen AU - Yan Lu AU - Ramesh Narayanan AU - Deanna N. Parke AU - Wei Li AU - Sunjoo Ahn AU - Duane D. Miller AU - James T. Dalton Y1 - 2011/07/08 UR - http://dmd.aspetjournals.org/content/early/2011/07/08/dmd.110.036616.abstract N2 - Microtubules are critical components of the cytoskeleton. Perturbing their function arrests the growth of a broad spectrum of cancer cell lines, making microtubules an excellent and established target for chemotherapy. All of the FDA-approved antitubulin agents bind to paclitaxel- or vinblastine-binding sites in tubulin. Due to the complexity of their structures, it is difficult to structurally modify the vinca alkaloids and taxanes and develop orally bioavailable agents. Antitubulin agents that target the colchicine-binding site in tubulin may provide a better opportunity to be developed for oral use due to their relatively simple structures and physicochemical properties. A potent antitubulin agent, 4-(3, 4, 5-trimethoxybenzoyl)-2-phenyl-thiazole (SMART-H), binding to the colchicine-binding site, was discovered in our laboratory. However, the bioavailability of SMART-H was low due to its poor solubility. Structural modification of SMART-H led to the development of ABI-274 (2-aryl-4-benzoyl-imidazole analog), with improved bioavailability and potency but still considerable first pass metabolism. A chlorine derivative (ABI-286), replacing the methyl site of ABI-274, resulted in 1.5-fold higher metabolic stability in vitro, and 1.8-fold lower clearance in rats in vivo, indicating that metabolic stability of ABI-274 can be extended by blocking benzylic hydroxylation. Overall, ABI-274 and ABI-286 provided 2.4- and 5.5-fold increases in exposure (AUC) after oral dosing in rats compared to SMART-H. Most importantly, the structural modifications did not compromise potency. ABI-286 exhibited moderate clearance, moderate volume of distribution, and acceptable oral bioavailability. This study provided the first evidence that ABI-286 may be the first member of a new class of orally bioavailable antitubulin agents. ER -