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-beta type I receptor inhibitor.
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.
Department of Medicinal Chemistry and Biology, GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. francoise.gellibert@gsk.com
Françoise
F
Gellibert
Anne-Charlotte
AC
de Gouville
James
J
Woolven
Neil
N
Mathews
Van-Loc
VL
Nguyen
Cécile
C
Bertho-Ruault
Angela
A
Patikis
Eugene T
ET
Grygielko
Nicholas J
NJ
Laping
Stéphane
S
Huet
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004128:Dimethylnitrosamine; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases; D011692:Puromycin Aminonucleoside; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C509927:4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; D001549:Benzamides; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011720:Pyrazoles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011692:Puromycin Aminonucleoside; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat; D004128:Dimethylnitrosamine