Substituted N-aryl-6-pyrimidinones: A new class of potent, selective, and orally active p38 MAP kinase inhibitors
Journal Article
·
· Bioorg. Med. Chem. Lett.
- Pfizer
A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-{alpha} in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- INDUSTRY
- OSTI ID:
- 1026534
- Journal Information:
- Bioorg. Med. Chem. Lett., Vol. 21, Issue (13) ; 07, 2011
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38[alpha] Mitogen-Activated Protein Kinase Inhibitors
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
Journal Article
·
Mon Jun 30 00:00:00 EDT 2008
· J. Med. Chem.
·
OSTI ID:1026534
+24 more
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase
Journal Article
·
Mon Oct 18 00:00:00 EDT 2010
· Bioorg. Med. Chem. Lett.
·
OSTI ID:1026534
+22 more
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
Journal Article
·
Mon Jan 28 00:00:00 EST 2019
· Journal of Medicinal Chemistry
·
OSTI ID:1026534
+27 more