Synthesis and biological evaluation of novel pyridazinone-based alpha4 integrin receptor antagonists
| Autor: | Yong Gong, Barbay Jk, Dennis J. Hlasta, Stephen M. Prouty, Scott A. Ballentine, Patricia Andrade-Gordon, Alexey B. Dyatkin, William Hageman, John A. Masucci, Rosemary J. Santulli, M. C. Fisher, Pamela J. Hornby, Wei He, N. H. Wallace, Bruce P. Damiano, Craig R. Schneider, Tamara A. Miskowski, Edward S. Kimball, Bruce E. Maryanoff |
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| Rok vydání: | 2006 |
| Předmět: |
Integrins
Umbilical Veins Phenylalanine Biological Availability Immunoglobulins Vascular Cell Adhesion Molecule-1 In Vitro Techniques Integrin alpha4beta1 Chemical synthesis Monocytes chemistry.chemical_compound Mice Structure-Activity Relationship Mucoproteins In vivo Amide Drug Discovery Cell Adhesion Animals Humans Prodrugs Lymphocytes Cell adhesion Receptor Chemistry Dextran Sulfate Endothelial Cells Esters Prodrug Colitis In vitro Rats Pyridazines Biochemistry Molecular Medicine K562 Cells Cell Adhesion Molecules Granulocytes |
| Zdroj: | Journal of medicinal chemistry. 49(11) |
| ISSN: | 0022-2623 |
| Popis: | A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model. |
| Databáze: | OpenAIRE |
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