TY - JOUR T1 - Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 742 LP - 750 DO - 10.1124/jpet.104.075648 VL - 312 IS - 2 AU - R. B. Pepinsky AU - W.-C. Lee AU - M. Cornebise AU - A. Gill AU - K. Wortham AU - L. L. Chen AU - D. R. Leone AU - K. Giza AU - B. M. Dolinski AU - S. Perper AU - C. Nickerson-Nutter AU - D. Lepage AU - A. Chakraborty AU - E. T. Whalley AU - R. C. Petter AU - S. P. Adams AU - R. R. Lobb AU - D. M. Scott Y1 - 2005/02/01 UR - http://jpet.aspetjournals.org/content/312/2/742.abstract N2 - Integrin α4β1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (KD of 9 pM) small molecule inhibitor of α4β1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (KD of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-a-week dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for α4β1. These studies demonstrate the feasibility of PEGylation of α4β1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing α4β1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases. ER -