Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties
| Autor: | Mark Cornebise, C. Nickerson-Nutter, Brian M. Dolinski, Stuart J. Perper, Steve Adams, Alan Gill, Diane R Leone, Doreen Lepage, Keith Giza, R. B. Pepinsky, L. L. Chen, Eric T. Whalley, Roy R. Lobb, K. Wortham, Petter Russell C, Daniel Scott, Wen-Cherng Lee, A. Chakraborty |
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| Rok vydání: | 2004 |
| Předmět: |
Encephalomyelitis
Autoimmune Experimental Injections Subcutaneous Anti-Inflammatory Agents Polyethylene glycol Integrin alpha4beta1 Pharmacology Polyethylene Glycols Jurkat Cells Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics In vivo Cell Adhesion medicine Animals Humans Paralysis Structure–activity relationship Lymphocyte Count Phenylurea Compounds Experimental autoimmune encephalomyelitis Myelin Basic Protein medicine.disease Small molecule In vitro Rats chemistry Rats Inbred Lew Drug Design Injections Intravenous Luminescent Measurements PEGylation Molecular Medicine Female Oligopeptides |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 312:742-750 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.104.075648 |
| Popis: | Integrin alpha4beta1 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 (K(D) of 9 pM) small molecule inhibitor of alpha4beta1. 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 (K(D) 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 alpha4beta1. These studies demonstrate the feasibility of PEGylation of alpha4beta1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing alpha4beta1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases. |
| Databáze: | OpenAIRE |
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