- 2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-β1 and activin A signalling
-
Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.
- Ciayadi, Rudy,Potdar, Mahesh,Walton, Kelly L.,Harrison, Craig A.,Kelso, Geoffrey F.,Harris, Simon J.,Hearn, Milton T.W.
-
supporting information; experimental part
p. 5642 - 5645
(2011/10/09)
-
- 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
-
Inhibitors of transforming growth factor β (TGF-β) 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.
- Gellibert, Fran?oise,De Gouville, Anne-Charlotte,Woolven, James,Mathews, Neil,Nguyen, Van-Loc,Bertho-Ruault, Cécile,Patikis, Angela,Grygielko, Eugene T.,Laping, Nicholas J.,Huet, Stéphane
-
p. 2210 - 2221
(2007/10/03)
-
- Pyrazole derivatives against tgf overexpression
-
Therapeutically active pyrazole derivatives of formula (I) wherein R1-R3 are as defined in the specification, processes for the preparation thereof, the use thereof in therapy, particularly in the treatment or prophylaxis of disorders characterised by overexpression of transforming growth factor β (TGF-β), and pharmaceutical compositions for use in such therapy, Formula (I)
- -
-
-
