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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 14, 2004; DOI: 10.1124/jpet.104.075648

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*Substance via MeSH


Received for publication August 9, 2004.
Revised October 13, 2004.
Accepted for publication October 13, 2004.

Design, Synthesis, and Analysis of a Polyethelene Glycol-modified (PEGylated) Small Molecule Inhibitor of Integrin {alpha}4{beta}1 with Improved Pharmaceutical Properties

R. B. PEPINSKY 1*, W-C. LEE 1, M. CORNEBISE 1, A. GILL 1, K. WORTHAM 1, L. L. CHEN 1, D. R. LEONE 1, K. GIZA 1, B. M. DOLINSKI 1, S. PERPER 1, C. NICKERSON-NUTTER 1, D. LEPAGE 1, A. CHAKRABORTY 1, E. T. WHALLEY 1, R. C. PETTER 1, S. P. ADAMS 1, R. R. LOBB 1, D. M. SCOTT 1

1 BIOGENIDEC

* Address correspondence to: E-mail: blake.pepinsky{at}biogenidec.com

Abstract

Integrin {alpha}4{beta}1 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 {alpha}4{beta}1. While 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 EAE at a 30-fold lower molar dose than the parent compound, and required only a once a week dosing regimen as compared to a daily treatment for BIO5192. Compound 2a-PEG was highly selective for a4b1. These studies demonstrate the feasibility of PEGylation of {alpha}4{beta}1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing {alpha}4{beta}1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.


Key words: BIO5192, EAE, PEGylation, VLA4 inhibitors, alpha4beta1 integrin, multiple schlerosis




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