Discovery of 4-{4-[3-(Pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): A Potent, Selective, and Orally Active Transforming Growth Factor-β Type I Receptor Inhibitor
| Autor: | James Michael Woolven, Eugene T. Grygielko, Françoise Gellibert, Neil Mathews, Stéphane Huet, Nicholas J. Laping, Angela Patikis, Cécile Bertho-Ruault, Anne-Charlotte de Gouville, Van-Loc Nguyen |
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| Rok vydání: | 2006 |
| Předmět: |
Liver Cirrhosis
Male Models Molecular medicine.medical_specialty Receptor Transforming Growth Factor-beta Type I Administration Oral Protein Serine-Threonine Kinases Puromycin Aminonucleoside Pyrazole Pharmacology Kidney Collagen Type I Dimethylnitrosamine Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Growth factor receptor Oral administration Internal medicine Drug Discovery medicine Animals Structure–activity relationship RNA Messenger Benzamide biology Chemistry Kidney metabolism Transforming growth factor beta Fibrosis Rats Collagen Type I alpha 1 Chain Endocrinology Puromycin Acute Disease Benzamides biology.protein Pyrazoles Molecular Medicine Activin Receptors Type I Receptors Transforming Growth Factor beta |
| Zdroj: | Journal of Medicinal Chemistry. 49:2210-2221 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis. |
| Databáze: | OpenAIRE |
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